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Huang Y, Zhai Y, Zhao D, Wu M, Shen Q, Zhao W, Wang Q, Yao L, Li W. UHPLC-Q Exactive-Orbitrap-MS and network pharmacology analyses to investigate the mechanism by which Danggui-Shaoyao-San affects 27-OHC-induced cell damage in SH-SY5Y/C6 coculture. BMC Complement Med Ther 2025; 25:75. [PMID: 39994624 PMCID: PMC11849221 DOI: 10.1186/s12906-025-04751-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 01/07/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Danggui-Shaoyao-San (DSS) is a classic Chinese medicine formula that has been extensively studied for its efficacy in treating Alzheimer's disease (AD). However, its mechanism of action is still unclear. METHODS In this study, UHPLC-Q Exactive-Orbitrap-MS was used to analyze and identify the compounds in DSS. Network pharmacology was used to analyze the common targets of drug-containing serum chemistries and AD, as well as the AD pathways in which drug-containing serum chemistries may be involved. The 27-OHC-induced SH-SY5Y/C6 coculture cell injury model was used to explore the mechanism of action of DSS in the treatment of AD. RESULTS UHPLC-Q Exactive-Orbitrap-MS analysis identified 73 chemical constituents in DSS aqueous extract and 39 compounds in drug-containing serum. According to network pharmacology analysis, DSS and AD share 181 common targets, with interleukin-6 (IL-6) and tumor necrosis factor (TNF) being the main effective targets. Furthermore, DSS may treat AD through the modulation of lipid metabolism-related pathways and the interleukin-17 (IL-17) signaling pathway. 27-hydroxycholesterol acid (27-OHC) significantly reduced the viability of SH-SY5Y cells and C6 cells in vitro, while DSS administration upregulated the expression of cytochrome P450 46A1 (CYP46A1) and cytochrome P450 7B1 (CYP7B1) enzymes and reduced cholesterol levels in SH-SY5Y cells. Additionally, DSS decreased reactive oxygen species (ROS) levels and increased glutathione (GSH) levels in coculture systems. DSS downregulated the expression of IL-17 in 27-OHC-injured SH-SY5Y cells and downregulated the expression of TNF-α, IL-6 and transforming growth factor-β1 (TGF-β1) in 27-OHC-injured C6 cells. CONCLUSION This study revealed the effective components, targets and mechanisms of DSS in the treatment of AD, highlighting the significant potential of DSS in treating this disease.
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Affiliation(s)
- Yi Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yingying Zhai
- School of Pharmacy, Xinyang Agriculture and Forestry University, Henan, China
| | - Di Zhao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mingan Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Shen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Zhao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Limei Yao
- School of Traditional Chinese Medicine Healthcare, Guangdong Food and Drug Vocational College, Tianhe District, 321 Longdong North Road, Guangzhou, 510520, China.
| | - Weirong Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Savulescu-Fiedler I, Dorobantu-Lungu LR, Dragosloveanu S, Benea SN, Dragosloveanu CDM, Caruntu A, Scheau AE, Caruntu C, Scheau C. The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms. Curr Issues Mol Biol 2025; 47:115. [PMID: 39996836 PMCID: PMC11853762 DOI: 10.3390/cimb47020115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/30/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
Cholesterol is an essential element for the development and normal function of the central nervous system. While peripheral cholesterol is influenced by liver metabolism and diet, brain cholesterol metabolism takes place in an isolated system due to the impermeability of the blood-brain barrier (BBB). However, cross-talk occurs between the brain and periphery, specifically through metabolites such as oxysterols that play key roles in regulating cholesterol balance. Several neurodegenerative conditions such as Alzheimer's disease or Parkinson's disease are considered to be affected by the loss of this balance. Also, the treatment of hypercholesterolemia needs to consider these discrete interferences between brain and peripheral cholesterol and the possible implications of each therapeutic approach. This is particularly important because of 27-hydroxycholesterol and 24-hydroxycholesterol, which can cross the BBB and are involved in cholesterol metabolism. This paper examines the metabolic pathways of cholesterol metabolism in the brain and periphery and focuses on the complex cross-talk between these metabolisms. Also, we emphasize the regulatory role of the BBB and the need for an integrated approach to cholesterol management.
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Affiliation(s)
- Ilinca Savulescu-Fiedler
- Department of Internal Medicine, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Internal Medicine and Cardiology, Coltea Clinical Hospital, 030167 Bucharest, Romania
| | - Luiza-Roxana Dorobantu-Lungu
- Department of Cardiology, Emergency Institute for Cardiovascular Diseases “C.C. Iliescu”, 022328 Bucharest, Romania
| | - Serban Dragosloveanu
- Department of Orthopaedics, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
- Department of Orthopaedics and Traumatology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Serban Nicolae Benea
- Department of Infectious Diseases, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Departament of Infectious Diseases, National Institute for Infectious Diseases “Prof. Dr. Matei Balș”, 021105 Bucharest, Romania
| | - Christiana Diana Maria Dragosloveanu
- Department of Ophthalmology, Faculty of Dentistry, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Ophthalmology, Clinical Hospital for Ophthalmological Emergencies, 010464 Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, “Carol Davila” Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, “Titu Maiorescu” University, 031593 Bucharest, Romania
| | - Andreea-Elena Scheau
- Department of Radiology and Medical Imaging, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Dermatology, “Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Cristian Scheau
- Department of Physiology, The “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Radiology and Medical Imaging, “Foisor” Clinical Hospital of Orthopaedics, Traumatology and Osteoarticular TB, 021382 Bucharest, Romania
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Martínez-Martos JM, Cantón-Habas V, Rich-Ruíz M, Reyes-Medina MJ, Ramírez-Expósito MJ, Carrera-González MDP. Sexual and Metabolic Differences in Hippocampal Evolution: Alzheimer's Disease Implications. Life (Basel) 2024; 14:1547. [PMID: 39768255 PMCID: PMC11677427 DOI: 10.3390/life14121547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/18/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
Sex differences in brain metabolism and their relationship to neurodegenerative diseases like Alzheimer's are an important emerging topic in neuroscience. Intrinsic anatomic and metabolic differences related to male and female physiology have been described, underscoring the importance of considering biological sex in studying brain metabolism and associated pathologies. The hippocampus is a key structure exhibiting sex differences in volume and connectivity. Adult neurogenesis in the dentate gyrus, dendritic spine density, and electrophysiological plasticity contribute to the hippocampus' remarkable plasticity. Glucose transporters GLUT3 and GLUT4 are expressed in human hippocampal neurons, with proper glucose metabolism being crucial for learning and memory. Sex hormones play a major role, with the aromatase enzyme that generates estradiol increasing in neurons and astrocytes as an endogenous neuroprotective mechanism. Inhibition of aromatase increases gliosis and neurodegeneration after brain injury. Genetic variants of aromatase may confer higher Alzheimer's risk. Estrogen replacement therapy in postmenopausal women prevents hippocampal hypometabolism and preserves memory. Insulin is also a key regulator of hippocampal glucose metabolism and cognitive processes. Dysregulation of the insulin-sensitive glucose transporter GLUT4 may explain the comorbidity between type II diabetes and Alzheimer's. GLUT4 colocalizes with the insulin-regulated aminopeptidase IRAP in neuronal vesicles, suggesting an activity-dependent glucose uptake mechanism. Sex differences in brain metabolism are an important factor in understanding neurodegenerative diseases, and future research must elucidate the underlying mechanisms and potential therapeutic implications of these differences.
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Affiliation(s)
- José Manuel Martínez-Martos
- Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaen, Las Lagunillas University Campus, 23009 Jaen, Spain; (J.M.M.-M.); (M.J.R.-E.)
| | - Vanesa Cantón-Habas
- Department of Nursing, Pharmacology and Physiotherapy, Faculty of Medicine and Nursing, University of Córdoba, 14004 Córdoba, Spain; (V.C.-H.); (M.R.-R.); (M.J.R.-M.)
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC) IMIBIC Building, Reina Sofia University Hospital, Av. Menéndez Pidal, s/n, 14004 Cordoba, Spain
| | - Manuel Rich-Ruíz
- Department of Nursing, Pharmacology and Physiotherapy, Faculty of Medicine and Nursing, University of Córdoba, 14004 Córdoba, Spain; (V.C.-H.); (M.R.-R.); (M.J.R.-M.)
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC) IMIBIC Building, Reina Sofia University Hospital, Av. Menéndez Pidal, s/n, 14004 Cordoba, Spain
| | - María José Reyes-Medina
- Department of Nursing, Pharmacology and Physiotherapy, Faculty of Medicine and Nursing, University of Córdoba, 14004 Córdoba, Spain; (V.C.-H.); (M.R.-R.); (M.J.R.-M.)
| | - María Jesús Ramírez-Expósito
- Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaen, Las Lagunillas University Campus, 23009 Jaen, Spain; (J.M.M.-M.); (M.J.R.-E.)
| | - María del Pilar Carrera-González
- Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, Faculty of Health Sciences, University of Jaen, Las Lagunillas University Campus, 23009 Jaen, Spain; (J.M.M.-M.); (M.J.R.-E.)
- Maimonides Institute of Biomedical Research of Córdoba (IMIBIC) IMIBIC Building, Reina Sofia University Hospital, Av. Menéndez Pidal, s/n, 14004 Cordoba, Spain
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Zhang D, Wang Z, Guo S, Sun Y, Zhou D, Li W, Yan J, Chen Y, Luo S, Huang G, Qian Z, Li Z. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography imaging reveals the protective effect of docosahexaenoic acid on glucose metabolism by reducing brain 27-hydroxycholesterol. Exp Gerontol 2024; 196:112577. [PMID: 39241991 DOI: 10.1016/j.exger.2024.112577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/04/2024] [Accepted: 09/03/2024] [Indexed: 09/09/2024]
Abstract
Total cholesterol (TC) and the cholesterol oxidation product 27-hydroxycholesterol (27-OHC) are both increased in the elderly. Accumulating evidence has linked 27-OHC to glucose metabolism in the brain, while docosahexaenoic acid (DHA) has been shown to positively regulate the 27-OHC levels. However, it is unclear whether DHA may affect glucose metabolism in the brain by regulating 27-OHC levels. In this study, we hypothesized that DHA supplementation would modulate TC levels and reduce 27-OHC levels, thereby improving brain glucose metabolism in SAMP8 mice. The mice were assigned into the Control group and DHA dietary supplementation group. The study evaluated cholesterol levels, 27-OHC levels, and glucose metabolism in the brain. The results showed that DHA supplementation decreased serum levels of TC, low-density lipoprotein cholesterol (LDL-C), and increased levels of high-density lipoprotein cholesterol (HDL-C); and improved the glucose-corrected standardized uptake value of cortex, hippocampus, and whole brain regions in SAMP8 mice. In conclusion, supplementation of DHA could regulate the cholesterol composition and reduce the level of 27-OHC, thereby improving brain glucose metabolism in SAMP8 mice.
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Affiliation(s)
- Dalong Zhang
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China.
| | - Zehao Wang
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
| | - Shuangshuang Guo
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
| | - Yue Sun
- Department of Public Health, School of Medicine, Ningbo University, Zhejiang 315211, China.
| | - Dezheng Zhou
- Department of Public Health, School of Medicine, Ningbo University, Zhejiang 315211, China.
| | - Wen Li
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, School of Public Health, Tianjin Medical University, Tianjin, China.
| | - Jing Yan
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, School of Public Health, Tianjin Medical University, Tianjin, China; Department of Social Medicine and Health Administration, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
| | - Yongjie Chen
- Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, School of Public Health, Tianjin Medical University, Tianjin, China; Department of Epidemiology & Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
| | - Suhui Luo
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, School of Public Health, Tianjin Medical University, Tianjin, China.
| | - Guowei Huang
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, School of Public Health, Tianjin Medical University, Tianjin, China.
| | - Zhiyong Qian
- Department of Toxicology, Tianjin Centers for Disease Control and Prevention, Tianjin 300011, China.
| | - Zhenshu Li
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Key Laboratory of Prevention and Control of Major Diseases in the Population, Ministry of Education, School of Public Health, Tianjin Medical University, Tianjin, China.
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5
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Ye H, Yang X, Feng B, Luo P, Torres Irizarry VC, Carrillo-Sáenz L, Yu M, Yang Y, Eappen BP, Munoz MD, Patel N, Schaul S, Ibrahimi L, Lai P, Qi X, Zhou Y, Kota M, Dixit D, Mun M, Liew CW, Jiang Y, Wang C, He Y, Xu P. 27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior. SCIENCE ADVANCES 2024; 10:eadi4746. [PMID: 38996023 PMCID: PMC11244552 DOI: 10.1126/sciadv.adi4746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 02/05/2024] [Indexed: 07/14/2024]
Abstract
Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.
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Affiliation(s)
- Hui Ye
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 639798, Singapore
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Xiaohua Yang
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Guangdong Laboratory of Lingnan Modern Agriculture and Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China
| | - Bing Feng
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA
| | - Pei Luo
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Guangdong Laboratory of Lingnan Modern Agriculture and Guangdong Province Key Laboratory of Animal Nutritional Regulation, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, 483 Wushan Road, Tianhe District, Guangzhou, Guangdong 510642, China
| | - Valeria C. Torres Irizarry
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Leslie Carrillo-Sáenz
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Meng Yu
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yongjie Yang
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Benjamin P. Eappen
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Marcos David Munoz
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Nirali Patel
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Sarah Schaul
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Lucas Ibrahimi
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Penghua Lai
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Xinyue Qi
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 639798, Singapore
| | - Yuliang Zhou
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 639798, Singapore
| | - Maya Kota
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Devin Dixit
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Madeline Mun
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Chong Wee Liew
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Yuwei Jiang
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Chunmei Wang
- Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
| | - Yanlin He
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA
| | - Pingwen Xu
- Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL 60612, USA
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Jaykumar AB, Binns D, Taylor CA, Anselmo A, Birnbaum SG, Huber KM, Cobb MH. WNKs regulate mouse behavior and alter central nervous system glucose uptake and insulin signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.09.598125. [PMID: 38915673 PMCID: PMC11195145 DOI: 10.1101/2024.06.09.598125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhances in vivo hippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary neuronal cultures and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.
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Affiliation(s)
- Ankita B. Jaykumar
- Departments of Pharmacology, UT Southwestern Medical Center, Dallas, USA
| | - Derk Binns
- Departments of Pharmacology, UT Southwestern Medical Center, Dallas, USA
| | - Clinton A. Taylor
- Departments of Pharmacology, UT Southwestern Medical Center, Dallas, USA
| | - Anthony Anselmo
- Departments of Pharmacology, UT Southwestern Medical Center, Dallas, USA
| | - Shari G. Birnbaum
- Departments of Peter O’Donnell Jr. Brain Institute and Psychiatry, UT Southwestern Medical Center, Dallas, USA
| | | | - Melanie H. Cobb
- Departments of Pharmacology, UT Southwestern Medical Center, Dallas, USA
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Liu LC, Liang JY, Liu YH, Liu B, Dong XH, Cai WH, Zhang N. The Intersection of cerebral cholesterol metabolism and Alzheimer's disease: Mechanisms and therapeutic prospects. Heliyon 2024; 10:e30523. [PMID: 38726205 PMCID: PMC11079309 DOI: 10.1016/j.heliyon.2024.e30523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/12/2024] Open
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly, the exact pathogenesis of which remains incompletely understood, and effective preventive and therapeutic drugs are currently lacking. Cholesterol plays a vital role in cell membrane formation and neurotransmitter synthesis, and its abnormal metabolism is associated with the onset of AD. With the continuous advancement of imaging techniques and molecular biology methods, researchers can more accurately explore the relationship between cholesterol metabolism and AD. Elevated cholesterol levels may lead to vascular dysfunction, thereby affecting neuronal function. Additionally, abnormal cholesterol metabolism may affect the metabolism of β-amyloid protein, thereby promoting the onset of AD. Brain cholesterol levels are regulated by multiple factors. This review aims to deepen the understanding of the subtle relationship between cholesterol homeostasis and AD, and to introduce the latest advances in cholesterol-regulating AD treatment strategies, thereby inspiring readers to contemplate deeply on this complex relationship. Although there are still many unresolved important issues regarding the risk of brain cholesterol and AD, and some studies may have opposite conclusions, further research is needed to enrich our understanding. However, these findings are expected to deepen our understanding of the pathogenesis of AD and provide important insights for the future development of AD treatment strategies targeting brain cholesterol homeostasis.
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Affiliation(s)
- Li-cheng Liu
- Pharmaceutical Branch, Harbin Pharmaceutical Group Co., Harbin, Heilongjiang Province, China
| | - Jun-yi Liang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Yan-hong Liu
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Bin Liu
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Xiao-hong Dong
- Jiamusi College, Heilongjiang University of Traditional Chinese Medicine, Jiamusi, Heilongjiang Province, China
| | - Wen-hui Cai
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province, China
| | - Ning Zhang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang Province, China
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Spanos F, Gerenu G, Goikolea J, Latorre-Leal M, Balleza-Tapia H, Gomez K, Álvarez-Jiménez L, Piras A, Gómez-Galán M, Fisahn A, Cedazo-Minguez A, Maioli S, Loera-Valencia R. Impaired astrocytic synaptic function by peripheral cholesterol metabolite 27-hydroxycholesterol. Front Cell Neurosci 2024; 18:1347535. [PMID: 38650656 PMCID: PMC11034371 DOI: 10.3389/fncel.2024.1347535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/19/2024] [Indexed: 04/25/2024] Open
Abstract
Astrocytes represent the most abundant cell type in the brain, where they play critical roles in synaptic transmission, cognition, and behavior. Recent discoveries show astrocytes are involved in synaptic dysfunction during Alzheimer's disease (AD). AD patients have imbalanced cholesterol metabolism, demonstrated by high levels of side-chain oxidized cholesterol known as 27-hydroxycholesterol (27-OH). Evidence from our laboratory has shown that elevated 27-OH can abolish synaptic connectivity during neuromaturation, but its effect on astrocyte function is currently unclear. Our results suggest that elevated 27-OH decreases the astrocyte function in vivo in Cyp27Tg, a mouse model of brain oxysterol imbalance. Here, we report a downregulation of glutamate transporters in the hippocampus of CYP27Tg mice together with increased GFAP. GLT-1 downregulation was also observed when WT mice were fed with high-cholesterol diets. To study the relationship between astrocytes and neurons, we have developed a 3D co-culture system that allows all the cell types from mice embryos to differentiate in vitro. We report that our 3D co-cultures reproduce the effects of 27-OH observed in 2D neurons and in vivo. Moreover, we found novel degenerative effects in astrocytes that do not appear in 2D cultures, together with the downregulation of glutamate transporters GLT-1 and GLAST. We propose that this transporter dysregulation leads to neuronal hyperexcitability and synaptic dysfunction based on the effects of 27-OH on astrocytes. Taken together, these results report a new mechanism linking oxysterol imbalance in the brain and synaptic dysfunction through effects on astrocyte function.
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Affiliation(s)
- Fokion Spanos
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Gorka Gerenu
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
- Department of Physiology, Biogipuzkoa Health Research Institute - Ikerbasque Basque foundation for Science and University of Basque Country, San Sebastian, Spain
- CIBERNED (Ministry of Economy and Competitiveness, Institute Carlos III), Madrid, Spain
| | - Julen Goikolea
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - María Latorre-Leal
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Hugo Balleza-Tapia
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Karen Gomez
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Laura Álvarez-Jiménez
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Antonio Piras
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Marta Gómez-Galán
- Anestesiologi Laboratory, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - André Fisahn
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Angel Cedazo-Minguez
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Silvia Maioli
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
| | - Raúl Loera-Valencia
- Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Center for Alzheimer Research, Stockholm, Sweden
- School of Medicine and Health Sciences, Tecnologico de Monterrey, Chihuahua, Mexico
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9
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Zhang X, Chen C, Liu Y. Navigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer's astrocytes. Alzheimers Res Ther 2024; 16:63. [PMID: 38521950 PMCID: PMC10960454 DOI: 10.1186/s13195-024-01430-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/13/2024] [Indexed: 03/25/2024]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia, and its underlying mechanisms have been a subject of great interest. The mainstream theory of AD pathology suggests that the disease is primarily associated with tau protein and amyloid-beta (Aβ). However, an increasing body of research has revealed that abnormalities in lipid metabolism may be an important event throughout the pathophysiology of AD. Astrocytes, as important members of the lipid metabolism network in the brain, play a significant role in this event. The study of abnormal lipid metabolism in astrocytes provides a new perspective for understanding the pathogenesis of AD. This review focuses on the abnormal metabolism of fatty acids (FAs) and cholesterol in astrocytes in AD, and discusses it from three perspectives: lipid uptake, intracellular breakdown or synthesis metabolism, and efflux transport. We found that, despite the accumulation of their own fatty acids, astrocytes cannot efficiently uptake fatty acids from neurons, leading to fatty acid accumulation within neurons and resulting in lipotoxicity. In terms of cholesterol metabolism, astrocytes exhibit a decrease in endogenous synthesis due to the accumulation of exogenous cholesterol. Through a thorough investigation of these metabolic abnormalities, we can provide new insights for future therapeutic strategies by literature review to navigate this complex metabolic maze and bring hope to patients with Alzheimer's disease.
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Affiliation(s)
- Xiaoyu Zhang
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Chuanying Chen
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
- School of Traditional Chinese Medicine, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, Guangdong, 510515, People's Republic of China
| | - Yi Liu
- Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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10
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Zhao X, Cai X, Zhu H, Dang Q, Yang Q, Zhu Y, Zhang Y, Zhang M, Jiang X, Hu Z, Wei Y, Xiao R, Yu H. 27-Hydroxycholesterol inhibits trophoblast fusion during placenta development by activating PI3K/AKT/mTOR signaling pathway. Arch Toxicol 2024; 98:849-863. [PMID: 38180513 DOI: 10.1007/s00204-023-03664-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/07/2023] [Indexed: 01/06/2024]
Abstract
Trophoblast cell syncytialization is essential for placental and fetal development. Abnormal trophoblast cell fusion leads to pregnancy pathologies, such as preeclampsia (PE), intrauterine growth restriction (IUGR), and miscarriage. 27-hydroxycholesterol (27-OHC) is the most abundant oxysterol in human peripheral blood synthesized by sterol 27-hydroxylase (CYP27A1) and is considered a critical mediator between hypercholesterolemia and a variety of related disorders. Gestational hypercholesterolemia was associated with spontaneous preterm delivery and low birth weight (LBW) in term infants, yet the mechanism is unclear. In this study, two trophoblast cell models and CD-1 mice were used to evaluate the effects of 27-OHC on trophoblast fusion during placenta development. Two different kinds of trophoblast cells received a dosage of 2.5, 5, or 10 uM 27-OHC. Three groups of pregnant mice were randomly assigned: control, full treatment (E0.5-E17.5), or late treatment (E13.5-E17.5). All mice received daily intraperitoneal injections of saline (control group) and 27-OHC (treatment group; 5.5 mg/kg). In vitro experiments, we found that 27-OHC inhibited trophoblast cell fusion in primary human trophoblasts (PHT) and forskolin (FSK)-induced BeWo cells. 27-OHC up-regulated the expression of the PI3K/AKT/mTOR signaling pathway-related proteins. Moreover, the PI3K inhibitor LY294002 rescued the inhibitory effect of 27-OHC. Inhibition of trophoblast cell fusion by 27-OHC was also observed in CD-1 mice. Furthermore, fetal weight and placental efficiency decreased and fetal blood vessel development was inhibited in pregnant mice treated with 27-OHC. This study was the first to prove that 27-OHC inhibits trophoblast cell fusion by Activating PI3K/AKT/mTOR signaling pathway. This study reveals a novel mechanism by which dyslipidemia during pregnancy results in adverse pregnancy outcomes.
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Affiliation(s)
- Xiaoyan Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Xiaxia Cai
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Haiyan Zhu
- FuXing Hospital, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Qinyu Dang
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Qian Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Yandi Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Yadi Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Mengling Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Xinyin Jiang
- Departments of Health and Nutrition Sciences, Brooklyn College of City University of New York, New York, NY, 11210, USA
| | - Zhuo Hu
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Yuchen Wei
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Rong Xiao
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Huanling Yu
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, People's Republic of China.
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11
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Wang T, Hao L, Yang K, Feng W, Guo Z, Liu M, Xiao R. Fecal microbiota transplantation derived from mild cognitive impairment individuals impairs cerebral glucose uptake and cognitive function in wild-type mice: Bacteroidetes and TXNIP-GLUT signaling pathway. Gut Microbes 2024; 16:2395907. [PMID: 39262376 PMCID: PMC11404573 DOI: 10.1080/19490976.2024.2395907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/23/2024] [Accepted: 08/16/2024] [Indexed: 09/13/2024] Open
Abstract
Gut microbiome dysbiosis has been widely implicated in cognitive impairment, but the identity of the specific bacterial taxa and mechanisms are not fully elucidated. Brain glucose hypometabolism coincides with the cognitive decline. This study explored the link among cognition, gut microbiota and glucose uptake based on the fecal microbiota transplantation from mild cognitive impairment individuals (MCI-FMT) and investigated whether similar mechanisms were involved in 27-hydroxycholesterol (27-OHC)-induced cognitive decline. Our results showed that the MCI-FMT mice exhibited learning and memory decline and morphological lesions in the brain and colon tissues. There were reduced 18F-fluorodeoxyglucose uptake, downregulated expression of glucose transporters (GLUT1,3,4) and upregulated negative regulator of glucose uptake (TXNIP) in the brain. MCI-FMT altered the bacterial composition and diversity of the recipient mice, and the microbial signatures highlighted by the increased abundance of Bacteroides recapitulated the negative effects of MCI bacterial colonization. However, inhibiting Bacteroidetes or TXNIP increased the expression of GLUT1 and GLUT4, significantly improving brain glucose uptake and cognitive performance in 27-OHC-treated mice. Our study verified that cognitive decline and abnormal cerebral glucose uptake were associated with gut microbiota dysbiosis; we also revealed the involvement of Bacteroidetes and molecular mechanisms of TXNIP-related glucose uptake in cognitive deficits caused by 27-OHC.
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Affiliation(s)
- Tao Wang
- School of Public Health, Capital Medical University, Beijing, China
| | - Ling Hao
- School of Public Health, Capital Medical University, Beijing, China
- Institute for Nutrition and Food Hygiene, Beijing Center for Disease Prevention and Control, Beijing, China
| | - Kexin Yang
- School of Public Health, Capital Medical University, Beijing, China
| | - Wenjing Feng
- School of Public Health, Capital Medical University, Beijing, China
| | - Zhiting Guo
- School of Public Health, Capital Medical University, Beijing, China
| | - Miao Liu
- School of Public Health, Capital Medical University, Beijing, China
| | - Rong Xiao
- School of Public Health, Capital Medical University, Beijing, China
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12
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Petrov AM. Oxysterols in Central and Peripheral Synaptic Communication. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:91-123. [PMID: 38036877 DOI: 10.1007/978-3-031-43883-7_6] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Cholesterol is a key molecule for synaptic transmission, and both central and peripheral synapses are cholesterol rich. During intense neuronal activity, a substantial portion of synaptic cholesterol can be oxidized by either enzymatic or non-enzymatic pathways to form oxysterols, which in turn modulate the activities of neurotransmitter receptors (e.g., NMDA and adrenergic receptors), signaling molecules (nitric oxide synthases, protein kinase C, liver X receptors), and synaptic vesicle cycling involved in neurotransmitters release. 24-Hydroxycholesterol, produced by neurons in the brain, could directly affect neighboring synapses and change neurotransmission. 27-Hydroxycholesterol, which can cross the blood-brain barrier, can alter both synaptogenesis and synaptic plasticity. Increased generation of 25-hydroxycholesterol by activated microglia and macrophages could link inflammatory processes to learning and neuronal regulation. Amyloids and oxidative stress can lead to an increase in the levels of ring-oxidized sterols and some of these oxysterols (4-cholesten-3-one, 5α-cholestan-3-one, 7β-hydroxycholesterol, 7-ketocholesterol) have a high potency to disturb or modulate neurotransmission at both the presynaptic and postsynaptic levels. Overall, oxysterols could be used as "molecular prototypes" for therapeutic approaches. Analogs of 24-hydroxycholesterol (SGE-301, SGE-550, SAGE718) can be used for correction of NMDA receptor hypofunction-related states, whereas inhibitors of cholesterol 24-hydroxylase, cholestane-3β,5α,6β-triol, and cholest-4-en-3-one oxime (olesoxime) can be utilized as potential anti-epileptic drugs and (or) protectors from excitotoxicity.
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Affiliation(s)
- Alexey M Petrov
- Laboratory of Biophysics of Synaptic Processes, Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", Kazan, RT, Russia.
- Kazan State Medial University, Kazan, RT, Russia.
- Kazan Federal University, Kazan, RT, Russia.
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13
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Ito T, Ichikawa T, Yamada M, Hashimoto Y, Fujino N, Numakura T, Sasaki Y, Suzuki A, Takita K, Sano H, Kyogoku Y, Saito T, Koarai A, Tamada T, Sugiura H. CYP27A1-27-hydroxycholesterol axis in the respiratory system contributes to house dust mite-induced allergic airway inflammation. Allergol Int 2024; 73:151-163. [PMID: 37607853 DOI: 10.1016/j.alit.2023.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND 27-Hydroxycholesterol (27-HC) derived from sterol 27-hydroxylase (CYP27A1) has pro-inflammatory biological activity and is associated with oxidative stress and chronic inflammation in COPD. However, the role of regulation of CYP27A1- 27-HC axis in asthma is unclear. This study aimed to elucidate the contribution of the axis to the pathophysiology of asthma. METHODS House dust mite (HDM) extract was intranasally administered to C57BL/6 mice and the expression of CYP27A1 in the airways was analyzed by immunostaining. The effect of pre-treatment with PBS or CYP27A1 inhibitors on the cell fraction in the bronchoalveolar lavage fluid (BALF) was analyzed in the murine model. In vitro, BEAS-2B cells were treated with HDM and the levels of CYP27A1 expression were examined. Furthermore, the effect of 27-HC on the expressions of E-cadherin and ZO-1 in the cells was analyzed. The amounts of RANTES and eotaxin from the 27-HC-treated cells were analyzed by ELISA. RESULTS The administration of HDM increased the expression of CYP27A1 in the airways of mice as well as the number of eosinophils in the BALF. CYP27A1 inhibitors ameliorated the HDM-induced increase in the number of eosinophils in the BALF. Treatment with HDM increased the expression of CYP27A1 in BEAS-2B cells. The administration of 27-HC to BEAS-2B cells suppressed the expression of E-cadherin and ZO-1, and augmented the production of RANTES and eotaxin. CONCLUSIONS The results of this study suggest that aeroallergen could enhance the induction of CYP27A1, leading to allergic airway inflammation and disruption of the airway epithelial tight junction through 27-HC production.
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Affiliation(s)
- Tatsunori Ito
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Ichikawa
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Mitsuhiro Yamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuichiro Hashimoto
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoya Fujino
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tadahisa Numakura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusaku Sasaki
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ayumi Suzuki
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Katsuya Takita
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hirohito Sano
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yorihiko Kyogoku
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takuya Saito
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Koarai
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tsutomu Tamada
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hisatoshi Sugiura
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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14
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Prajapat M, Kaur G, Choudhary G, Pahwa P, Bansal S, Joshi R, Batra G, Mishra A, Singla R, Kaur H, Prabha PK, Patel AP, Medhi B. A systematic review for the development of Alzheimer's disease in in vitro models: a focus on different inducing agents. Front Aging Neurosci 2023; 15:1296919. [PMID: 38173557 PMCID: PMC10761490 DOI: 10.3389/fnagi.2023.1296919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Alzheimer's disease (AD) is the most common progressive neurodegenerative disease and is associated with dementia. Presently, various chemical and environmental agents are used to induce in-vitro models of Alzheimer disease to investigate the efficacy of different therapeutic drugs. We screened literature from databases such as PubMed, ScienceDirect, and Google scholar, emphasizing the diverse targeting mechanisms of neuro degeneration explored in in-vitro models. The results revealed studies in which different types of chemicals and environmental agents were used for in-vitro development of Alzheimer-targeting mechanisms of neurodegeneration. Studies using chemically induced in-vitro AD models included in this systematic review will contribute to a deeper understanding of AD. However, none of these models can reproduce all the characteristics of disease progression seen in the majority of Alzheimer's disease subtypes. Additional modifications would be required to replicate the complex conditions of human AD in an exact manner. In-vitro models of Alzheimer's disease developed using chemicals and environmental agents are instrumental in providing insights into the disease's pathophysiology; therefore, chemical-induced in-vitro AD models will continue to play vital role in future AD research. This systematic screening revealed the pivotal role of chemical-induced in-vitro AD models in advancing our understanding of AD pathophysiology and is therefore important to understand the potential of these chemicals in AD pathogenesis.
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Affiliation(s)
| | - Gurjeet Kaur
- Department of Pharmacology, PGIMER, Chandigarh, India
| | | | - Paras Pahwa
- Department of Pharmacology, PGIMER, Chandigarh, India
| | - Seema Bansal
- MM College of Pharmacy, Maharishi Markandeshwar (DU) University, Mullana, Ambala, India
| | - Rupa Joshi
- Department of Pharmacology, PGIMER, Chandigarh, India
| | - Gitika Batra
- Department of Neurology, PGIMER, Chandigarh, India
| | - Abhishek Mishra
- Department of Biomedical Sciences, University of Minnesota, Minneapolis, MN, United States
| | - Rubal Singla
- Department of Pharmacology, PGIMER, Chandigarh, India
| | | | | | | | - Bikash Medhi
- Department of Pharmacology, PGIMER, Chandigarh, India
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15
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Petek B, Häbel H, Xu H, Villa-Lopez M, Kalar I, Hoang MT, Maioli S, Pereira JB, Mostafaei S, Winblad B, Gregoric Kramberger M, Eriksdotter M, Garcia-Ptacek S. Statins and cognitive decline in patients with Alzheimer's and mixed dementia: a longitudinal registry-based cohort study. Alzheimers Res Ther 2023; 15:220. [PMID: 38115091 PMCID: PMC10731754 DOI: 10.1186/s13195-023-01360-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 11/28/2023] [Indexed: 12/21/2023]
Abstract
BACKGROUND Disturbances in brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer's disease (AD). Lipid-lowering medications could interfere with neurodegenerative processes in AD through cholesterol metabolism or other mechanisms. OBJECTIVE To explore the association between the use of lipid-lowering medications and cognitive decline over time in a cohort of patients with AD or mixed dementia with indication for lipid-lowering treatment. METHODS A longitudinal cohort study using the Swedish Registry for Cognitive/Dementia Disorders, linked with other Swedish national registries. Cognitive trajectories evaluated with mini-mental state examination (MMSE) were compared between statin users and non-users, individual statin users, groups of statins and non-statin lipid-lowering medications using mixed-effect regression models with inverse probability of drop out weighting. A dose-response analysis included statin users compared to non-users. RESULTS Our cohort consisted of 15,586 patients with mean age of 79.5 years at diagnosis and a majority of women (59.2 %). A dose-response effect was demonstrated: taking one defined daily dose of statins on average was associated with 0.63 more MMSE points after 3 years compared to no use of statins (95% CI: 0.33;0.94). Simvastatin users showed 1.01 more MMSE points (95% CI: 0.06;1.97) after 3 years compared to atorvastatin users. Younger (< 79.5 years at index date) simvastatin users had 0.80 more MMSE points compared to younger atorvastatin users (95% CI: 0.05;1.55) after 3 years. Simvastatin users had 1.03 more MMSE points (95% CI: 0.26;1.80) compared to rosuvastatin users after 3 years. No differences regarding statin lipophilicity were observed. The results of sensitivity analysis restricted to incident users were not consistent. CONCLUSIONS Some patients with AD or mixed dementia with indication for lipid-lowering medication may benefit cognitively from statin treatment; however, further research is needed to clarify the findings of sensitivity analyses.
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Affiliation(s)
- Bojana Petek
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
| | - Henrike Häbel
- Medical Statistics Unit, Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, Stockholm, Sweden
| | - Hong Xu
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Marta Villa-Lopez
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, University Complutense of Madrid, Madrid, Spain
- Department of Neurology, University of Alberta Hospital, Edmonton, Canada
| | - Irena Kalar
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Minh Tuan Hoang
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Silvia Maioli
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Joana B Pereira
- Division of Neuro, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
| | - Shayan Mostafaei
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Bengt Winblad
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Aging and Inflammation Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Milica Gregoric Kramberger
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Maria Eriksdotter
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
- Aging and Inflammation Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Sara Garcia-Ptacek
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
- Aging and Inflammation Theme, Karolinska University Hospital, Stockholm, Sweden.
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16
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Hao L, Wang L, Ju M, Feng W, Guo Z, Sun X, Xiao R. 27-Hydroxycholesterol impairs learning and memory ability via decreasing brain glucose uptake mediated by the gut microbiota. Biomed Pharmacother 2023; 168:115649. [PMID: 37806088 DOI: 10.1016/j.biopha.2023.115649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023] Open
Abstract
Brain glucose hypometabolism is a significant manifestation of Alzheimer's disease (AD). 27-hydroxycholesterol (27-OHC) and the gut microbiota have been recognized as factors possibly influencing the pathogenesis of AD. This study aimed to investigate the link between 27-OHC, the gut microbiota, and brain glucose uptake in AD. Here, 6-month-old male C57BL/6 J mice were treated with sterile water or antibiotic cocktails, with or without 27-OHC and/or 27-OHC synthetic enzyme CYP27A1 inhibitor anastrozole (ANS). The gut microbiota, brain glucose uptake levels, and memory ability were measured. We observed that 27-OHC altered microbiota composition, damaged brain tissue structures, decreased the 2-deoxy-2-[18 F] fluorodeoxyglucose (18F-FDG) uptake value, downregulated the gene expression of glucose transporter type 4 (GLUT4), reduced the colocalization of GLUT1/glial fibrillary acidic protein (GFAP) in the hippocampus, and impaired spatial memory. ANS reversed the effects of 27-OHC. The antibiotic-treated mice did not exhibit similar results after 27-OHC treatment. This study reveals a potential molecular mechanism wherein 27-OHC-induced memory impairment might be linked to reduced brain glucose uptake, mediated by the gut microbiota.
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Affiliation(s)
- Ling Hao
- School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China
| | - Lijing Wang
- School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China
| | - Mengwei Ju
- School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China
| | - Wenjing Feng
- School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China
| | - Zhiting Guo
- School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China
| | - Xuejing Sun
- School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China
| | - Rong Xiao
- School of Public Health, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing 100069, China.
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17
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Goikolea J, Latorre-Leal M, Tsagkogianni C, Pikkupeura S, Gulyas B, Cedazo-Minguez A, Loera-Valencia R, Björkhem I, Rodriguez Rodriguez P, Maioli S. Different effects of CYP27A1 and CYP7B1 on cognitive function: Two mouse models in comparison. J Steroid Biochem Mol Biol 2023; 234:106387. [PMID: 37648096 DOI: 10.1016/j.jsbmb.2023.106387] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/27/2023] [Indexed: 09/01/2023]
Abstract
The oxysterol 27-hydroxycholesterol (27OHC) is produced by the enzyme sterol 27-hydroxylase (Cyp27A1) and is mainly catabolized to 7α-Hydroxy-3-oxo-4-cholestenoic acid (7-HOCA) by the enzyme cytochrome P-450 oxysterol 7α-hydroxylase (Cyp7B1). 27OHC is mostly produced in the liver and can reach the brain by crossing the blood-brain barrier. A large body of evidence shows that CYP27A1 overexpression and high levels of 27OHC have a detrimental effect on the brain, causing cognitive and synaptic dysfunction together with a decrease in glucose uptake in mice. In this work, we analyzed two mouse models with high levels of 27OHC: Cyp7B1 knock-out mice and CYP27A1 overexpressing mice. Despite the accumulation of 27OHC in both models, Cyp7B1 knock-out mice maintained intact learning and memory capacities, neuronal morphology, and brain glucose uptake over time. Neurons treated with the Cyp7B1 metabolite 7-HOCA did not show changes in synaptic genes and 27OHC-treated Cyp7B1 knock-out neurons could not counteract 27OHC detrimental effects. This suggests that 7-HOCA and Cyp7B1 deletion in neurons do not mediate the neuroprotective effects observed in Cyp7B1 knock-out animals. RNA-seq of neuronal nuclei sorted from Cyp7B1 knock-out brains revealed upregulation of genes likely to confer neuroprotection to these animals. Differently from Cyp7B1 knock-out mice, transcriptomic data from CYP27A1 overexpressing neurons showed significant downregulation of genes associated with synaptic function and several metabolic processes. Our results suggest that the differences observed in the two models may be mediated by the higher levels of Cyp7B1 substrates such as 25-hydroxycholesterol and 3β-Adiol in the knock-out mice and that CYP27A1 overexpressing mice may be a more suitable model for studying 27-OHC-specific signaling. We believe that future studies on Cyp7B1 and Cyp27A1 will contribute to a better understanding of the pathogenic mechanisms of neurodegenerative diseases like Alzheimer's disease and may lead to potential new therapeutic approaches.
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Affiliation(s)
- Julen Goikolea
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden
| | - Maria Latorre-Leal
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden
| | - Christina Tsagkogianni
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden
| | - Sonja Pikkupeura
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden
| | - Balazs Gulyas
- Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden
| | - Angel Cedazo-Minguez
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden
| | - Raul Loera-Valencia
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden; Tecnologico de Monterrey, School of Medicine and Health Sciences, Chihuahua, Mexico
| | - Ingemar Björkhem
- Karolinska Institutet, Department of Laboratory Medicine, Huddinge, Sweden
| | - Patricia Rodriguez Rodriguez
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden
| | - Silvia Maioli
- Karolinska Institutet, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Stockholm, Sweden.
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18
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Vini R, Jaikumar VS, Remadevi V, Ravindran S, Azeez JM, Sasikumar A, Sundaram S, Sreeja S. Urolithin A: A promising selective estrogen receptor modulator and 27-hydroxycholesterol attenuator in breast cancer. Phytother Res 2023; 37:4504-4521. [PMID: 37345359 DOI: 10.1002/ptr.7919] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 05/08/2023] [Accepted: 05/27/2023] [Indexed: 06/23/2023]
Abstract
27-hydroxycholesterol (27-HC) is an oxysterol that acts as an endogenous selective estrogen receptor modulator (SERM), and its adverse effects on breast cancer via the estrogen receptor (ER) have provided new insights into the pathology of cholesterol-linked breast cancer. Our earlier in vitro experiments showed that the methanolic extract of pomegranate could exhibit SERM properties and compete with 27-HC. The major constituents of pomegranate are ellagitannins and ellagic acid, which are converted into urolithins by the colonic microbiota. In recent years, urolithins, especially urolithin A (UA) and urolithin B (UB), have been reported to have a plethora of advantageous effects, including antiproliferative and estrogenic activities. In this study, we attempted to determine the potential of urolithins in antagonizing and counteracting the adverse effects of 27-HC in breast cancer cells. Our findings suggested that UA had an antiproliferative capacity and attenuated the proliferative effects of 27-HC, resulting in subsequent loss of membrane potential and apoptosis in breast cancer cells. Further, UA induced estrogen response element (ERE) transcriptional activity and modulated estrogen-responsive genes, exhibiting a SERM-like response concerning receptor binding. Our in vivo hollow fiber assay results showed a loss of cell viability in breast cancer cells upon UA consumption, as well as a reduction in 27-HC-induced proliferative activity. Additionally, it was shown that UA did not induce uterine proliferation or alter blood biochemical parameters. Based on these findings, we can conclude that UA has the potential to act as a potent estrogen receptor alpha (ERα) modulator and 27-HC antagonist. UA is safe to consume and is very well tolerated. This study further opens up the potential of UA as ER modulator and its benefits in estrogen-dependent tissues.
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Affiliation(s)
- Ravindran Vini
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
- Research Centre, University of Kerala, Thiruvananthapuram, India
| | - Vishnu Sunil Jaikumar
- Animal Research Facility, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
| | - Viji Remadevi
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
- Research Centre, University of Kerala, Thiruvananthapuram, India
| | - Swathy Ravindran
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
| | - Juberiya M Azeez
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
- Research Centre, University of Kerala, Thiruvananthapuram, India
| | - Anjana Sasikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
| | - Shankar Sundaram
- Department of Pathology, Government Medical College, Kottayam, India
| | - Sreeharshan Sreeja
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
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19
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Hjazi A, Ahsan M, Alghamdi MI, Kareem AK, Al-Saidi DN, Qasim MT, Romero-Parra RM, Zabibah RS, Ramírez-Coronel AA, Mustafa YF, Hosseini-Fard SR, Karampoor S, Mirzaei R. Unraveling the impact of 27-hydroxycholesterol in autoimmune diseases: Exploring promising therapeutic approaches. Pathol Res Pract 2023; 248:154737. [PMID: 37542860 DOI: 10.1016/j.prp.2023.154737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/07/2023]
Abstract
The role of 27-hydroxycholesterol (27-OHC) in autoimmune diseases has become a subject of intense research in recent years. This oxysterol, derived from cholesterol, has been identified as a significant player in modulating immune responses and inflammation. Its involvement in autoimmune pathogenesis has drawn attention to its potential as a therapeutic target for managing autoimmune disorders effectively. 27-OHC, an oxysterol derived from cholesterol, has emerged as a key player in modulating immune responses and inflammatory processes. It exerts its effects through various mechanisms, including activation of nuclear receptors, interaction with immune cells, and modulation of neuroinflammation. Additionally, 27-OHC has been implicated in the dysregulation of lipid metabolism, neurotoxicity, and blood-brain barrier (BBB) disruption. Understanding the intricate interplay between 27-OHC and autoimmune diseases, particularly neurodegenerative disorders, holds promise for developing targeted therapeutic strategies. Additionally, emerging evidence suggests that 27-OHC may interact with specific receptors and transcription factors, thus influencing gene expression and cellular processes in autoimmune disorders. Understanding the intricate mechanisms by which 27-OHC influences immune dysregulation and tissue damage in autoimmune diseases is crucial for developing targeted therapeutic interventions. Further investigations into the molecular pathways and signaling networks involving 27-OHC are warranted to unravel its full potential as a therapeutic target in autoimmune diseases, thereby offering new avenues for disease intervention and management.
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Affiliation(s)
- Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Maria Ahsan
- King Edward Medical University Lahore, Pakistan
| | - Mohammed I Alghamdi
- Department of Computer Science, Al-Baha University, Al-Baha City, Kingdom of Saudi Arabia
| | - A K Kareem
- Biomedical Engineering Department, Al-Mustaqbal University College, Babylon, Iraq
| | - Dahlia N Al-Saidi
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Andrés Alexis Ramírez-Coronel
- Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Ecuador; University of Palermo, Buenos Aires, Argentina; Research group in educational statistics, National University of Education, Azogues, Ecuador; Epidemiology and Biostatistics Research Group, CES University, Colombia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
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20
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Clark C, Gholam M, Zullo L, Kerksiek A, Castelao E, von Gunten A, Preisig M, Lütjohann D, Popp J. Plant sterols and cholesterol metabolism are associated with five-year cognitive decline in the elderly population. iScience 2023; 26:106740. [PMID: 37250771 PMCID: PMC10209479 DOI: 10.1016/j.isci.2023.106740] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 02/13/2023] [Accepted: 04/20/2023] [Indexed: 05/31/2023] Open
Abstract
Dysregulations in cholesterol metabolism are associated with neurodegenerative and vascular pathologies, and dementia. Diet-derived plant sterols (phytosterols) have cholesterol-lowering, anti-inflammatory, and antioxidant properties and may interfere with neurodegeneration and cognitive decline. Here we performed multivariate analysis in 720 individuals enrolled in a population-based prospective study to determine whether circulating cholesterol precursors and metabolites, triglycerides, and phytosterols, are associated with cognitive impairment and decline in the older population. We report specific dysregulations of endogenous cholesterol synthesis and metabolism, and diet-derived phytosterols, and their changes over time associated with cognitive impairment, and decline in the general population. These findings suggest circulating sterols levels could be considered in risk evaluation and are relevant for the development of strategies to prevent cognitive decline in older people.
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Affiliation(s)
- Christopher Clark
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Lenggstrasse 31, PO Box 363, 8032 Zürich, Switzerland
- Department of Mathematics, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Mehdi Gholam
- Department of Mathematics, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Leonardo Zullo
- Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Route de Cery 60, 1008 Prilly, Switzerland
| | - Anja Kerksiek
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Enrique Castelao
- Department of Psychiatry, Center for Research in Psychiatric Epidemiology and Psychopathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Armin von Gunten
- Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Route de Cery 60, 1008 Prilly, Switzerland
| | - Martin Preisig
- Department of Psychiatry, Center for Research in Psychiatric Epidemiology and Psychopathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Julius Popp
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zürich, Lenggstrasse 31, PO Box 363, 8032 Zürich, Switzerland
- Old Age Psychiatry, Department of Psychiatry, Lausanne University Hospital, Route de Cery 60, 1008 Prilly, Switzerland
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21
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Zhao T, Miao H, Song Z, Li Y, Xia N, Zhang Z, Zhang H. Metformin alleviates the cognitive impairment induced by benzo[a]pyrene via glucolipid metabolism regulated by FTO/FoxO6 pathway in mice. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:69192-69204. [PMID: 37133670 DOI: 10.1007/s11356-023-27303-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/25/2023] [Indexed: 05/04/2023]
Abstract
Benzo[a]pyrene (B[a]P) is neurotoxic; however, the mechanism and prevention are still unclear. In this study, we assessed the intervention effect of metformin (MET) on cognitive dysfunction in mice induced by B[a]P from the perspective of glucolipid metabolism. Forty-two male healthy ICR mice were randomly categorized into 6 groups and were gavaged with B[a]P (0, 2.5, 5, or 10 mg/kg), 45 times for 90 days. The controls were gavaged with edible peanut oil, and the intervention groups were co-treated with B[a]P (10 mg/kg) and MET (200 or 300 mg/kg). We assessed the cognitive function of mice, observed the pathomorphological and ultrastructural changes, and detected neuronal apoptosis and glucolipid metabolism. Results showed that B[a]P dose-dependently induced cognitive impairment, neuronal damage, glucolipid metabolism disorder in mice, and enhanced proteins of fat mass and obesity-associated protein (FTO) and forkhead box protein O6 (FoxO6) in the cerebral cortex and liver, which were alleviated by the MET intervention. The findings indicated the critical role of glucolipid metabolism disorder in the cognitive impairment in mice caused by B[a]P and the prevention of MET against B[a]P neurotoxicity by regulating glucolipid metabolism via restraining FTO/FoxO6 pathway. The finding provides a scientific basis for the neurotoxicity and prevention strategies of B[a]P.
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Affiliation(s)
- Tingyi Zhao
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Huide Miao
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Zhanfei Song
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Yangyang Li
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Na Xia
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Zhiyan Zhang
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China
| | - Hongmei Zhang
- Department of Environmental Health, School of Public Health, Shanxi Medical University, 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China.
- Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Taiyuan, China.
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22
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Mou Y, Nandi G, Mukte S, Chai E, Chen Z, Nielsen JE, Nielsen TT, Criscuolo C, Blackstone C, Fraidakis MJ, Li XJ. Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients. Orphanet J Rare Dis 2023; 18:72. [PMID: 37024986 PMCID: PMC10080795 DOI: 10.1186/s13023-023-02666-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 03/11/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Biallelic mutations in CYP27A1 and CYP7B1, two critical genes regulating cholesterol and bile acid metabolism, cause cerebrotendinous xanthomatosis (CTX) and hereditary spastic paraplegia type 5 (SPG5), respectively. These rare diseases are characterized by progressive degeneration of corticospinal motor neuron axons, yet the underlying pathogenic mechanisms and strategies to mitigate axonal degeneration remain elusive. METHODS To generate induced pluripotent stem cell (iPSC)-based models for CTX and SPG5, we reprogrammed patient skin fibroblasts into iPSCs by transducing fibroblast cells with episomal vectors containing pluripotency factors. These patient-specific iPSCs, as well as control iPSCs, were differentiated into cortical projection neurons (PNs) and examined for biochemical alterations and disease-related phenotypes. RESULTS CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases. Notably, the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons. To further examine underlying disease mechanisms, we developed CYP7B1 knockout human embryonic stem cell (hESC) lines using CRISPR-cas9-mediated gene editing and, following differentiation, examined hESC-derived cortical PNs. Knockout of CYP7B1 resulted in similar axonal vesiculation and degeneration in human cortical PN axons, confirming a cause-effect relationship between gene deficiency and axonal degeneration. Interestingly, CYP7B1 deficiency led to impaired neurofilament expression and organization as well as axonal degeneration, which could be rescued with CDCA, establishing a new disease mechanism and therapeutic target to mitigate axonal degeneration. CONCLUSIONS Our data demonstrate disease-specific lipid disturbances and axonopathy mechanisms in human pluripotent stem cell-based neuronal models of CTX and SPG5 and identify CDCA, an established treatment of CTX, as a potential pharmacotherapy for SPG5. We propose this novel treatment strategy to rescue axonal degeneration in SPG5, a currently incurable condition.
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Affiliation(s)
- Yongchao Mou
- Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Ghata Nandi
- Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA
| | - Sukhada Mukte
- Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA
| | - Eric Chai
- Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA
| | - Zhenyu Chen
- Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA
| | - Jorgen E Nielsen
- Neurogenetics Clinic & Research Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Troels T Nielsen
- Neurogenetics Clinic & Research Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Chiara Criscuolo
- Department of Neuroscience, Reproductive Sciences and Odontostomatology, Federico II University, Naples, Italy
| | - Craig Blackstone
- Movement Disorders Division, Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA
- MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Boston, MA, 02129, USA
| | - Matthew J Fraidakis
- Rare Neurological Diseases Unit, Department of Neurology, Attikon University Hospital, Medical School of the University of Athens, Athens, Greece
| | - Xue-Jun Li
- Department of Biomedical Sciences, University of Illinois College of Medicine Rockford, Rockford, IL, 61107, USA.
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.
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23
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Alanko V, Gaminde-Blasco A, Quintela-López T, Loera-Valencia R, Solomon A, Björkhem I, Cedazo-Minguez A, Maioli S, Tabacaru G, Latorre-Leal M, Matute C, Kivipelto M, Alberdi E, Sandebring-Matton A. 27-hydroxycholesterol promotes oligodendrocyte maturation: Implications for hypercholesterolemia-associated brain white matter changes. Glia 2023; 71:1414-1428. [PMID: 36779429 DOI: 10.1002/glia.24348] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 01/19/2023] [Accepted: 01/23/2023] [Indexed: 02/14/2023]
Abstract
Oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) is a potential link between hypercholesterolemia and neurodegenerative diseases since unlike peripheral cholesterol, 27-OH is transported across the blood-brain barrier. However, the effects of high 27-OH levels on oligodendrocyte function remain unexplored. We hypothesize that during hypercholesterolemia 27-OH may impact oligodendrocytes and myelin and thus contribute to the disconnection of neural networks in neurodegenerative diseases. To test this idea, we first investigated the effects of 27-OH in cultured oligodendrocytes and found that it induces cell death of immature O4+ /GalC+ oligodendrocytes along with stimulating differentiation of PDGFR+ oligodendrocyte progenitors (OPCs). Next, transgenic mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioral testing and their brains were immunohistochemically stained and lysed for immunoblotting. Chronic exposure to 27-OH in mice resulted in increased myelin basic protein (MBP) but not 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) or myelin oligodendrocyte glycoprotein (MOG) levels in the corpus callosum and cerebral cortex. Intriguingly, we also found impairment of spatial learning suggesting that subtle changes in myelinated axons of vulnerable areas like the hippocampus caused by 27-OH may contribute to impaired cognition. Finally, we found that 27-OH levels in cerebrospinal fluid from memory clinic patients were associated with levels of the myelination regulating CNPase, independently of Alzheimer's disease markers. Thus, 27-OH promotes OPC differentiation and is toxic to immature oligodendrocytes as well as it subtly alters myelin by targeting oligodendroglia. Taken together, these data indicate that hypercholesterolemia-derived higher 27-OH levels change the oligodendrocytic capacity for appropriate myelin remodeling which is a crucial factor in neurodegeneration and aging.
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Affiliation(s)
- Vilma Alanko
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden.,Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Adhara Gaminde-Blasco
- Department of Neuroscience, University of Basque Country (UPV/EHU) and CIBERNED, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Tania Quintela-López
- Department of Neuroscience, University of Basque Country (UPV/EHU) and CIBERNED, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Raúl Loera-Valencia
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Alina Solomon
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden.,Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.,Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK
| | - Ingemar Björkhem
- Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden
| | - Angel Cedazo-Minguez
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Silvia Maioli
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Graziella Tabacaru
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - María Latorre-Leal
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Carlos Matute
- Department of Neuroscience, University of Basque Country (UPV/EHU) and CIBERNED, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Miia Kivipelto
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden.,Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland.,Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK.,Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Elena Alberdi
- Department of Neuroscience, University of Basque Country (UPV/EHU) and CIBERNED, Leioa, Spain.,Achucarro Basque Center for Neuroscience, Leioa, Spain
| | - Anna Sandebring-Matton
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden.,Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden.,Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK
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24
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Akt-mediated mitochondrial metabolism regulates proplatelet formation and platelet shedding post vasopressin exposure. JOURNAL OF THROMBOSIS AND HAEMOSTASIS : JTH 2023; 21:344-358. [PMID: 36700501 DOI: 10.1016/j.jtha.2022.11.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/15/2022] [Accepted: 11/15/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND Platelet shedding from mature megakaryocytes (MKs) in thrombopoiesis is the critical step for elevating circulating platelets fast and efficiently, however, the underlying mechanism is still not well-illustrated, and the therapeutic targets and candidates are even less. OBJECTIVES In order to investigate the mechanisms for platelet shedding after vasopressin treatment and find new therapeutic targets for thrombocytopenia. METHODS Platelet production was evaluated both in vivo and in vitro after arginine vasopressin (AVP) administration. The underlying biological mechanism of AVP-triggered thrombopoiesis were then investigated by a series of molecular and bioinformatics techniques. RESULTS it is observed that proplatelet formation and platelet shedding in the final stages of thrombopoiesis promoted by AVP, an endogenous hormone, can quickly increases peripheral platelets. This rapid elevation is thus able to speed up platelet recovery after radiation as expected. The mechanism analysis reveal that proplatelet formation and platelet release from mature MKs facilitated by AVP is mainly mediated by Akt-regulated mitochondrial metabolism. In particular, phosphorylated Akt regulates mitochondrial metabolism through driving the association of hexokinase-2 with mitochondrial voltage dependent anion channel-1 in AVP-mediated thrombopoiesis. Further studies suggest that this interaction is stabilized by IκBα, the expression of which is controlled by insulin-regulated membrane aminopeptidase. CONCLUSION these data demonstrate that phosphorylated Akt-mediated mitochondrial metabolism regulates platelet shedding from MKs in response to AVP, which will provide new therapeutic targets and further drug discovery clues for thrombocytopenia treatment.
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Ventriculoperitoneal Shunt Treatment Increases 7 Alpha Hy-Droxy-3-Oxo-4-Cholestenoic Acid and 24-Hydroxycholesterol Concentrations in Idiopathic Normal Pressure Hydrocephalus. Brain Sci 2022; 12:brainsci12111450. [DOI: 10.3390/brainsci12111450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/26/2022] [Accepted: 10/26/2022] [Indexed: 11/16/2022] Open
Abstract
Idiopathic normal pressure hydrocephalus (iNPH) is the most common form of hydrocephalus in the adult population, and is often treated with cerebrospinal fluid (CSF) drainage using a ventriculoperitoneal (VP) shunt. Symptoms of iNPH include gait impairment, cognitive decline, and urinary incontinence. The pathophysiology behind the symptoms of iNPH is still unknown, and no reliable biomarkers have been established to date. The aim of this study was to investigate the possible use of the oxysterols as biomarkers in this disease. CSF levels of the oxysterols 24S- and 27-hydroxycholesterol, as well as the major metabolite of 27-hydroxycholesterol, 7 alpha hydroxy-3-oxo-4-cholestenoic acid (7HOCA), were measured in iNPH-patients before and after treatment with a VP-shunt. Corresponding measurements were also performed in healthy controls. VP-shunt treatment significantly increased the levels of 7HOCA and 24S-hydroxycholesterol in CSF (p = 0.014 and p = 0.037, respectively). The results are discussed in relation to the beneficial effects of VP-shunt treatment. Furthermore, the possibility that CSF drainage may reduce an inhibitory effect of transiently increased pressure on the metabolic capacity of neuronal cells in the brain is discussed. This capacity includes the elimination of cholesterol by the 24S-hydroxylase mechanisms.
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Engel MG, Smith J, Mao K, Quipildor GF, Cui MH, Gulinello M, Branch CA, Gandy SE, Huffman DM. Evidence for preserved insulin responsiveness in the aging rat brain. GeroScience 2022; 44:2491-2508. [PMID: 35798912 PMCID: PMC9768080 DOI: 10.1007/s11357-022-00618-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/27/2022] [Indexed: 01/06/2023] Open
Abstract
Insulin appears to exert salutary effects in the central nervous system (CNS). Thus, brain insulin resistance has been proposed to play a role in brain aging and dementia but is conceptually complex and unlikely to fit classic definitions established in peripheral tissues. Thus, we sought to characterize brain insulin responsiveness in young (4-5 months) and old (24 months) FBN male rats using a diverse set of assays to determine the extent to which insulin effects in the CNS are impaired with age. When performing hyperinsulinemic-euglycemic clamps in rats, intracerebroventricular (ICV) infusion of insulin in old animals improved peripheral insulin sensitivity by nearly two-fold over old controls and comparable to young rats, suggesting preservation of this insulin-triggered response in aging per se (p < 0.05). We next used an imaging-based approach by comparing ICV vehicle versus insulin and performed resting state functional magnetic resonance imaging (rs-fMRI) to evaluate age- and insulin-related changes in network connectivity within the default mode network. In aging, lower connectivity between the mesial temporal (MT) region and other areas, as well as reduced MT signal complexity, was observed in old rats, which correlated with greater cognitive deficits in old. Despite these stark differences, ICV insulin failed to elicit any significant alteration to the BOLD signal in young rats, while a significant deviation of the BOLD signal was observed in older animals, characterized by augmentation in regions of the septal nucleus and hypothalamus, and reduction in thalamus and nucleus accumbens. In contrast, ex vivo stimulation of hippocampus with 10 nM insulin revealed increased Akt activation in young (p < 0.05), but not old rats. Despite similar circulating levels of insulin and IGF-1, cerebrospinal fluid concentrations of these ligands were reduced with age. Thus, these data highlight the complexity of capturing brain insulin action and demonstrate preserved or heightened brain responses to insulin with age, despite dampened canonical signaling, thereby suggesting impaired CNS input of these ligands may be a feature of reduced brain insulin action, providing further rationale for CNS replacement strategies.
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Affiliation(s)
- Matthew G Engel
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Ave, Golding Building Room 201, BronxBronx, NY, 10461, USA
| | - Jeremy Smith
- Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA, USA
| | - Kai Mao
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Ave, Golding Building Room 201, BronxBronx, NY, 10461, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Gabriela Farias Quipildor
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Ave, Golding Building Room 201, BronxBronx, NY, 10461, USA
| | - Min-Hui Cui
- Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Maria Gulinello
- Dominick S. Purpura Department of Neuroscience, Behavioral Core Facility, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Craig A Branch
- Department of Radiology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Samuel E Gandy
- Department of Neurology and the Mount Sinai Center for Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry and the Mount Sinai Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Derek M Huffman
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Ave, Golding Building Room 201, BronxBronx, NY, 10461, USA.
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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Dias IH, Shokr H, Shephard F, Chakrabarti L. Oxysterols and Oxysterol Sulfates in Alzheimer’s Disease Brain and Cerebrospinal Fluid. J Alzheimers Dis 2022; 87:1527-1536. [PMID: 35491790 PMCID: PMC9277668 DOI: 10.3233/jad-220083] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Background: Brain cholesterol levels are tightly regulated but increasing evidence indicates that cholesterol metabolism may drive Alzheimer’s disease (AD)-associated pathological changes. Recent advances in understanding of mitochondrial dysfunction in AD brain have presented a vital role played by mitochondria in oxysterol biosynthesis and their involvement in pathophysiology. Oxysterol accumulation in brain is controlled by various enzymatic pathways including sulfation. While research into oxysterol is under the areas of active investigation, there is less evidence for oxysterol sulfate levels in human brain. Objective: This study investigates the hypothesis that AD brain oxysterol detoxification via sulfation is impaired in later stages of disease resulting in oxysterol accumulation. Methods: Lipids were extracted from postmortem frozen brain tissue and cerebrospinal (CSF) from late- (Braak stage III-IV) and early- (Braak stage I-II) stage AD patients. Samples were spiked with internal standards prior to lipid extraction. Oxysterols were enriched with a two-step solid phase extraction using a polymeric SPE column and further separation was achieved by LC-MS/MS. Results: Oxysterols, 26-hydroxycholesterol (26-OHC), 25-hydroxycholesterol (25-OHC), and 7-oxycholesterol levels were higher in brain tissue and mitochondria extracted from late-stage AD brain tissue except for 24S-hydroxycholesterol, which was decreased in late AD. However, oxysterol sulfates are significantly lower in the AD frontal cortex. Oxysterols, 25-OHC, and 7-oxocholesterol was higher is CSF but 26-OHC and oxysterol sulfate levels were not changed. Conclusion: Our results show oxysterol metabolism is altered in AD brain mitochondria, favoring synthesis of 26-OHC, 25-OHC, and 7-oxocholesterol, and this may influence brain mitochondrial function and acceleration of the disease.
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Affiliation(s)
- Irundika H.K. Dias
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, UK
| | - Hala Shokr
- Manchester Pharmacy School, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Freya Shephard
- Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Lisa Chakrabarti
- Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
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28
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Wu M, Zhai Y, Liang X, Chen W, Lin R, Ma L, Huang Y, Zhao D, Liang Y, Zhao W, Fang J, Fang S, Chen Y, Wang Q, Li W. Connecting the Dots Between Hypercholesterolemia and Alzheimer’s Disease: A Potential Mechanism Based on 27-Hydroxycholesterol. Front Neurosci 2022; 16:842814. [PMID: 35464321 PMCID: PMC9021879 DOI: 10.3389/fnins.2022.842814] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/01/2022] [Indexed: 12/13/2022] Open
Abstract
Alzheimer’s disease (AD), the most common cause of dementia, is a complex and multifactorial disease involving genetic and environmental factors, with hypercholesterolemia considered as one of the risk factors. Numerous epidemiological studies have reported a positive association between AD and serum cholesterol levels, and experimental studies also provide evidence that elevated cholesterol levels accelerate AD pathology. However, the underlying mechanism of hypercholesterolemia accelerating AD pathogenesis is not clear. Here, we review the metabolism of cholesterol in the brain and focus on the role of oxysterols, aiming to reveal the link between hypercholesterolemia and AD. 27-hydroxycholesterol (27-OHC) is the major peripheral oxysterol that flows into the brain, and it affects β-amyloid (Aβ) production and elimination as well as influencing other pathogenic mechanisms of AD. Although the potential link between hypercholesterolemia and AD is well established, cholesterol-lowering drugs show mixed results in improving cognitive function. Nevertheless, drugs that target cholesterol exocytosis and conversion show benefits in improving AD pathology. Herbs and natural compounds with cholesterol-lowering properties also have a potential role in ameliorating cognition. Collectively, hypercholesterolemia is a causative risk factor for AD, and 27-OHC is likely a potential mechanism for hypercholesterolemia to promote AD pathology. Drugs that regulate cholesterol metabolism are probably beneficial for AD, but more research is needed to unravel the mechanisms involved in 27-OHC, which may lead to new therapeutic strategies for AD.
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Affiliation(s)
- Mingan Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yingying Zhai
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoyi Liang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weichun Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ruiyi Lin
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Linlin Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Di Zhao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong Liang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei Zhao
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiansong Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuhuan Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yunbo Chen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Qi Wang,
| | - Weirong Li
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
- Weirong Li,
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Nunes VS, da Silva Ferreira G, Quintão ECR. Cholesterol metabolism in aging simultaneously altered in liver and nervous system. Aging (Albany NY) 2022; 14:1549-1561. [PMID: 35130181 PMCID: PMC8876915 DOI: 10.18632/aging.203880] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/08/2021] [Indexed: 11/25/2022]
Abstract
In humans, aging, triggers increased plasma concentrations of triglycerides, cholesterol, low-density lipoproteins and lower capacity of high-density lipoproteins to remove cellular cholesterol. Studies in rodents showed that aging led to cholesterol accumulation in the liver and decrease in the brain with reduced cholesterol synthesis and increased levels of cholesterol 24-hydroxylase, an enzyme responsible for removing cholesterol from the brain. Liver diseases are also related to brain aging, inducing changes in cholesterol metabolism in the brain and liver of rats. It has been suggested that late onset Alzheimer's disease is associated with metabolic syndrome. Non-alcoholic fatty liver is associated with lower total brain volume in the Framingham Heart Study offspring cohort study. Furthermore, disorders of cholesterol homeostasis in the adult brain are associated with neurological diseases such as Niemann-Pick, Alzheimer, Parkinson, Huntington and epilepsy. Apolipoprotein E (apoE) is important in transporting cholesterol from astrocytes to neurons in the etiology of sporadic Alzheimer's disease, an aging-related dementia. Desmosterol and 24S-hydroxycholesterol are reduced in ApoE KO hypercholesterolemic mice. ApoE KO mice have synaptic loss, cognitive dysfunction, and elevated plasma lipid levels that can affect brain function. In contrast to cholesterol itself, there is a continuous uptake of 27- hydroxycholesterol in the brain as it crosses the blood-brain barrier and this flow can be an important link between intra- and extracerebral cholesterol homeostasis. Not surprisingly, changes in cholesterol metabolism occur simultaneously in the liver and nervous tissues and may be considered possible biomarkers of the liver and nervous system aging.
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Affiliation(s)
- Valéria Sutti Nunes
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Bazil
| | - Guilherme da Silva Ferreira
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Bazil
| | - Eder Carlos Rocha Quintão
- Laboratorio de Lipides (LIM10), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Bazil
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30
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Maioli S, Leander K, Nilsson P, Nalvarte I. Estrogen receptors and the aging brain. Essays Biochem 2021; 65:913-925. [PMID: 34623401 PMCID: PMC8628183 DOI: 10.1042/ebc20200162] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 12/14/2022]
Abstract
The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior. Circulating sex hormones decrease in the course of aging, more rapidly at menopause in women, and slower in men. This review will discuss what this drop entails in terms of modulating neuroprotection and resilience in the aging brain downstream of spatiotemporal estrogen receptor alpha (ERα) and beta (ERβ) signaling, as well as in terms of the sex differences observed in Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, controversies related to ER expression in the brain will be discussed. Understanding the spatiotemporal signaling of sex hormones in the brain can lead to more personalized prevention strategies or therapies combating neurodegenerative diseases.
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Affiliation(s)
- Silvia Maioli
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Karin Leander
- Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Per Nilsson
- Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Ivan Nalvarte
- Department of Biosciences and Nutrition, Karolinska Institutet, 141 57 Huddinge, Sweden
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31
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Loera-Valencia R, Ismail MAM, Goikolea J, Lodeiro M, Mateos L, Björkhem I, Puerta E, Romão MA, Gomes CM, Merino-Serrais P, Maioli S, Cedazo-Minguez A. Hypercholesterolemia and 27-Hydroxycholesterol Increase S100A8 and RAGE Expression in the Brain: a Link Between Cholesterol, Alarmins, and Neurodegeneration. Mol Neurobiol 2021; 58:6063-6076. [PMID: 34449045 PMCID: PMC8639576 DOI: 10.1007/s12035-021-02521-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/04/2021] [Indexed: 12/20/2022]
Abstract
Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer's disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown. We used a high-fat/high-cholesterol diet in mice to study the effects of hypercholesterolemia over the alarmin S100A8 cascade in the hippocampus. Using CYP27Tg, a transgenic mouse model, we show that the hypercholesterolemia influence on the brain is mediated by the excess of 27-hydroxycholesterol (27-OH), a cholesterol metabolite. We also employed an acute model of 27-OH intraventricular injection in the brain to study RAGE and S100A8 response. We used primary cultures of neurons and astrocytes to study the effect of high levels of 27-OH over the S100A8 alarmin cascade. We report that a high-fat/high-cholesterol diet leads to an increase in S100A8 production in the brain. In CYP27Tg, we report an increase of S100A8 and its receptor RAGE in the hippocampus under elevated 27-OH in the brain. Using siRNA, we found that 27-OH upregulation of RAGE in astrocytes and neurons is mediated by the nuclear receptor RXRγ. Silencing RXRγ in neurons prevented 27-OH-mediated upregulation of RAGE. These results show that S100A8 alarmin and RAGE respond to high levels of 27-OH in the brain in both neurons and astrocytes through RXRγ. Our study supports the notion that 27-OH mediates detrimental effects of hypercholesterolemia to the brain via alarmin signaling.
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Affiliation(s)
- Raúl Loera-Valencia
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Muhammad-Al-Mustafa Ismail
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Julen Goikolea
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Maria Lodeiro
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Laura Mateos
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Ingemar Björkhem
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden
| | - Elena Puerta
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain
| | - Mariana A. Romão
- Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Departamento de Química E Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Cláudio M. Gomes
- Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Departamento de Química E Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Paula Merino-Serrais
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
- Laboratorio Cajal de Circuitos Corticales (CTB), Universidad Politécnica de Madrid, Madrid, Spain
- Departamento de Neurobiología Funcional y de Sistemas, Instituto Cajal, CSIC, Madrid, Spain
| | - Silvia Maioli
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
| | - Angel Cedazo-Minguez
- Division of Neurogeriatrics, Department of Neurobiology Care Sciences and Society, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden
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Staurenghi E, Giannelli S, Testa G, Sottero B, Leonarduzzi G, Gamba P. Cholesterol Dysmetabolism in Alzheimer's Disease: A Starring Role for Astrocytes? Antioxidants (Basel) 2021; 10:antiox10121890. [PMID: 34943002 PMCID: PMC8750262 DOI: 10.3390/antiox10121890] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 01/19/2023] Open
Abstract
In recent decades, the impairment of cholesterol metabolism in the pathogenesis of Alzheimer’s disease (AD) has been intensively investigated, and it has been recognized to affect amyloid β (Aβ) production and clearance, tau phosphorylation, neuroinflammation and degeneration. In particular, the key role of cholesterol oxidation products, named oxysterols, has emerged. Brain cholesterol metabolism is independent from that of peripheral tissues and it must be preserved in order to guarantee cerebral functions. Among the cells that help maintain brain cholesterol homeostasis, astrocytes play a starring role since they deliver de novo synthesized cholesterol to neurons. In addition, other physiological roles of astrocytes are to modulate synaptic transmission and plasticity and support neurons providing energy. In the AD brain, astrocytes undergo significant morphological and functional changes that contribute to AD onset and development. However, the extent of this contribution and the role played by oxysterols are still unclear. Here we review the current understanding of the physiological role exerted by astrocytes in the brain and their contribution to AD pathogenesis. In particular, we focus on the impact of cholesterol dysmetabolism on astrocyte functions suggesting new potential approaches to develop therapeutic strategies aimed at counteracting AD development.
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33
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Komleva YK, Potapenko IV, Lopatina OL, Gorina YV, Chernykh A, Khilazheva ED, Salmina AB, Shuvaev AN. NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms222111588. [PMID: 34769018 PMCID: PMC8583950 DOI: 10.3390/ijms222111588] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. METHODS To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR. RESULTS We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.
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Affiliation(s)
- Yulia K. Komleva
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University Named after Prof. V.F. Voino-Yasenetsky, 660022 Krasnoyarsk, Russia; (O.L.L.); (Y.V.G.); (E.D.K.)
- Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia; (I.V.P.); (A.C.); (A.B.S.); (A.N.S.)
- Correspondence:
| | - Ilia V. Potapenko
- Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia; (I.V.P.); (A.C.); (A.B.S.); (A.N.S.)
| | - Olga L. Lopatina
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University Named after Prof. V.F. Voino-Yasenetsky, 660022 Krasnoyarsk, Russia; (O.L.L.); (Y.V.G.); (E.D.K.)
- Shared Research Center for Molecular and Cellular Technologies, 660022 Krasnoyarsk, Russia
| | - Yana V. Gorina
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University Named after Prof. V.F. Voino-Yasenetsky, 660022 Krasnoyarsk, Russia; (O.L.L.); (Y.V.G.); (E.D.K.)
- Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia; (I.V.P.); (A.C.); (A.B.S.); (A.N.S.)
| | - Anatoly Chernykh
- Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia; (I.V.P.); (A.C.); (A.B.S.); (A.N.S.)
| | - Elena D. Khilazheva
- Department of Biochemistry, Medical, Pharmaceutical & Toxicological Chemistry, Krasnoyarsk State Medical University Named after Prof. V.F. Voino-Yasenetsky, 660022 Krasnoyarsk, Russia; (O.L.L.); (Y.V.G.); (E.D.K.)
- Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia; (I.V.P.); (A.C.); (A.B.S.); (A.N.S.)
| | - Alla B. Salmina
- Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia; (I.V.P.); (A.C.); (A.B.S.); (A.N.S.)
- Laboratory of Experimental Brain Cytology, Division of Brain Sciences, Research Center of Neurology, 125367 Moscow, Russia
| | - Anton N. Shuvaev
- Research Institute of Molecular Medicine and Pathobiochemistry, 660022 Krasnoyarsk, Russia; (I.V.P.); (A.C.); (A.B.S.); (A.N.S.)
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Brain Renin-Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms221810139. [PMID: 34576302 PMCID: PMC8468637 DOI: 10.3390/ijms221810139] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/12/2021] [Accepted: 09/14/2021] [Indexed: 12/15/2022] Open
Abstract
The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer's disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.
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How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors. Prog Cardiovasc Dis 2021; 67:65-74. [DOI: 10.1016/j.pcad.2020.12.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 12/22/2020] [Indexed: 12/20/2022]
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Folick A, Koliwad SK, Valdearcos M. Microglial Lipid Biology in the Hypothalamic Regulation of Metabolic Homeostasis. Front Endocrinol (Lausanne) 2021; 12:668396. [PMID: 34122343 PMCID: PMC8191416 DOI: 10.3389/fendo.2021.668396] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/05/2021] [Indexed: 12/18/2022] Open
Abstract
In mammals, myeloid cells help maintain the homeostasis of peripheral metabolic tissues, and their immunologic dysregulation contributes to the progression of obesity and associated metabolic disease. There is accumulating evidence that innate immune cells also serve as functional regulators within the mediobasal hypothalamus (MBH), a critical brain region controlling both energy and glucose homeostasis. Specifically, microglia, the resident parenchymal myeloid cells of the CNS, play important roles in brain physiology and pathology. Recent studies have revealed an expanding array of microglial functions beyond their established roles as immune sentinels, including roles in brain development, circuit refinement, and synaptic organization. We showed that microglia modulate MBH function by transmitting information resulting from excess nutrient consumption. For instance, microglia can sense the excessive consumption of saturated fats and instruct neurons within the MBH accordingly, leading to responsive alterations in energy balance. Interestingly, the recent emergence of high-resolution single-cell techniques has enabled specific microglial populations and phenotypes to be profiled in unprecedented detail. Such techniques have highlighted specific subsets of microglia notable for their capacity to regulate the expression of lipid metabolic genes, including lipoprotein lipase (LPL), apolipoprotein E (APOE) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). The discovery of this transcriptional signature highlights microglial lipid metabolism as a determinant of brain health and disease pathogenesis, with intriguing implications for the treatment of brain disorders and potentially metabolic disease. Here we review our current understanding of how changes in microglial lipid metabolism could influence the hypothalamic control of systemic metabolism.
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Affiliation(s)
- Andrew Folick
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Suneil K. Koliwad
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Martin Valdearcos
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
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Schwab N, Ju Y, Hazrati LN. Early onset senescence and cognitive impairment in a murine model of repeated mTBI. Acta Neuropathol Commun 2021; 9:82. [PMID: 33964983 PMCID: PMC8106230 DOI: 10.1186/s40478-021-01190-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/03/2021] [Indexed: 12/19/2022] Open
Abstract
Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell–cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.
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Gamba P, Giannelli S, Staurenghi E, Testa G, Sottero B, Biasi F, Poli G, Leonarduzzi G. The Controversial Role of 24-S-Hydroxycholesterol in Alzheimer's Disease. Antioxidants (Basel) 2021; 10:antiox10050740. [PMID: 34067119 PMCID: PMC8151638 DOI: 10.3390/antiox10050740] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 04/29/2021] [Accepted: 05/03/2021] [Indexed: 01/19/2023] Open
Abstract
The development of Alzheimer’s disease (AD) is influenced by several events, among which the dysregulation of cholesterol metabolism in the brain plays a major role. Maintenance of brain cholesterol homeostasis is essential for neuronal functioning and brain development. To maintain the steady-state level, excess brain cholesterol is converted into the more hydrophilic metabolite 24-S-hydroxycholesterol (24-OHC), also called cerebrosterol, by the neuron-specific enzyme CYP46A1. A growing bulk of evidence suggests that cholesterol oxidation products, named oxysterols, are the link connecting altered cholesterol metabolism to AD. It has been shown that the levels of some oxysterols, including 27-hydroxycholesterol, 7β-hydroxycholesterol and 7-ketocholesterol, significantly increase in AD brains contributing to disease progression. In contrast, 24-OHC levels decrease, likely due to neuronal loss. Among the different brain oxysterols, 24-OHC is certainly the one whose role is most controversial. It is the dominant oxysterol in the brain and evidence shows that it represents a signaling molecule of great importance for brain function. However, numerous studies highlighted the potential role of 24-OHC in favoring AD development, since it promotes neuroinflammation, amyloid β (Aβ) peptide production, oxidative stress and cell death. In parallel, 24-OHC has been shown to exert several beneficial effects against AD progression, such as preventing tau hyperphosphorylation and Aβ production. In this review we focus on the current knowledge of the controversial role of 24-OHC in AD pathogenesis, reporting a detailed overview of the findings about its levels in different AD biological samples and its noxious or neuroprotective effects in the brain. Given the relevant role of 24-OHC in AD pathophysiology, its targeting could be useful for disease prevention or slowing down its progression.
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Chai SY, Gutiérrez-de-Terán H, Stratikos E. Editorial: Physiological, Pathological Roles and Pharmacology of Insulin Regulated Aminopeptidase. Front Mol Biosci 2021; 8:685101. [PMID: 33968999 PMCID: PMC8102722 DOI: 10.3389/fmolb.2021.685101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 03/30/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Siew Yeen Chai
- Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | | | - Efstratios Stratikos
- Biochemistry Laboratory, Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece
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Sandebring-Matton A, Goikolea J, Björkhem I, Paternain L, Kemppainen N, Laatikainen T, Ngandu T, Rinne J, Soininen H, Cedazo-Minguez A, Solomon A, Kivipelto M. 27-Hydroxycholesterol, cognition, and brain imaging markers in the FINGER randomized controlled trial. Alzheimers Res Ther 2021; 13:56. [PMID: 33676572 PMCID: PMC7937194 DOI: 10.1186/s13195-021-00790-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 02/15/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND 27-Hydroxycholesterol (27-OH), the main circulating oxysterol in humans and the potential missing link between peripheral hypercholesterolemia and Alzheimer's disease (AD), has not been investigated previously in relation to cognition and neuroimaging markers in the context of preventive interventions. METHODS The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older individuals (60-77 years) at increased risk for dementia but without dementia or substantial cognitive impairment from the general population. Participants were randomized to a multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice) in a 1:1 ratio. Outcome assessors were masked to group allocation. This FINGER exploratory sub-study included 47 participants with measures of 27-OH, cognition, brain MRI, brain FDG-PET, and PiB-PET. Linear regression models were used to assess the cross-sectional and longitudinal associations between 27-OH, cognition, and neuroimaging markers, considering several potential confounders/intervention effect modifiers. RESULTS 27-OH reduction during the intervention was associated with improvement in cognition (especially memory). This was not observed in the control group. The intervention reduced 27-OH particularly in individuals with the highest 27-OH levels and younger age. No associations were found between changes in 27-OH levels and neuroimaging markers. However, at baseline, a higher 27-OH was associated with lower total gray matter and hippocampal volume, and lower cognitive scores. These associations were unaffected by total cholesterol levels. While sex seemed to influence associations at baseline, it did not affect longitudinal associations. CONCLUSION 27-OH appears to be a marker not only for dementia/AD risk, but also for monitoring the effects of preventive interventions on cholesterol metabolism. TRIAL REGISTRATION ClinicalTrials.gov , NCT01041989 . Registered on 4 January 2010.
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Affiliation(s)
- Anna Sandebring-Matton
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden.
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden.
| | - Julen Goikolea
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Ingemar Björkhem
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Laura Paternain
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Nina Kemppainen
- Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland
- Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Tiina Laatikainen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Joint Municipal Authority for North Karelia Social and Health Services, Joensuu, Finland
- Public Health Promotion Unit, Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Tiia Ngandu
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
- Public Health Promotion Unit, Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Juha Rinne
- Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Hilkka Soininen
- Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland
- Neurocenter, Neurology Kuopio University Hospital, Kuopio, Finland
| | - Angel Cedazo-Minguez
- Division of Neurogeriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
| | - Alina Solomon
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
- Institute of Clinical Medicine/Neurology, University of Eastern Finland, Kuopio, Finland
- Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK
| | - Miia Kivipelto
- Division of Clinical Geriatrics, Center for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
- Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, UK
- Theme Aging, Karolinska University Hospital, Stockholm, Sweden
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High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus. Sci Rep 2021; 11:3736. [PMID: 33580102 PMCID: PMC7881004 DOI: 10.1038/s41598-021-83008-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/25/2021] [Indexed: 12/16/2022] Open
Abstract
Alterations in brain cholesterol homeostasis in midlife are correlated with a higher risk of developing Alzheimer’s disease (AD). However, global cholesterol-lowering therapies have yielded mixed results when it comes to slowing down or preventing cognitive decline in AD. We used the transgenic mouse model Cyp27Tg, with systemically high levels of 27-hydroxycholesterol (27-OH) to examine long-term potentiation (LTP) in the hippocampal CA1 region, combined with dendritic spine reconstruction of CA1 pyramidal neurons to detect morphological and functional synaptic alterations induced by 27-OH high levels. Our results show that elevated 27-OH levels lead to enhanced LTP in the Schaffer collateral-CA1 synapses. This increase is correlated with abnormally large dendritic spines in the stratum radiatum. Using immunohistochemistry for synaptopodin (actin-binding protein involved in the recruitment of the spine apparatus), we found a significantly higher density of synaptopodin-positive puncta in CA1 in Cyp27Tg mice. We hypothesize that high 27-OH levels alter synaptic potentiation and could lead to dysfunction of fine-tuned processing of information in hippocampal circuits resulting in cognitive impairment. We suggest that these alterations could be detrimental for synaptic function and cognition later in life, representing a potential mechanism by which hypercholesterolemia could lead to alterations in memory function in neurodegenerative diseases.
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Parrado-Fernandez C, Leoni V, Saeed A, Rodriguez-Rodriguez P, Sandebring-Matton A, Córdoba-Beldad CM, Bueno P, Gali CC, Panzenboeck U, Cedazo-Minguez A, Björkhem I. Sex difference in flux of 27-hydroxycholesterol into the brain. Br J Pharmacol 2021; 178:3194-3204. [PMID: 33345295 PMCID: PMC8359195 DOI: 10.1111/bph.15353] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 11/30/2020] [Accepted: 12/05/2020] [Indexed: 01/21/2023] Open
Abstract
Background and Purpose The cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is believed to reflect the integrity of the blood–brain barrier (BBB). Recently, we reported that QAlb is lower in females. This may be important for uptake of neurotoxic 27‐hydroxycholesterol (27OH) by the brain in particular because plasma levels of 27OH are higher in males. We studied sex differences in the relation between CSF and plasma levels of 27OH and its major metabolite 7α‐hydroxy‐3‐oxo‐4‐cholestenoic acid (7HOCA) with QAlb. We tested the possibility of sex differences in the brain metabolism of 27OH and if its flux into the brain disrupted integrity of the BBB. Experimental Approach We have examined our earlier studies looking for sex differences in CSF levels of oxysterols and their relation to QAlb. We utilized an in vitro model for the BBB with primary cultured brain endothelial cells to test if 27OH has a disruptive effect on this barrier. We measured mRNA and protein levels of CYP7B1 in autopsy brain samples. Key Results The correlation between CSF levels of 27OH and QAlb was higher in males whereas, with 7HOCA, the correlation was higher in females. No significant sex difference in the expression of CYP7B1 mRNA in brain autopsy samples. A correlation was found between plasma levels of 27OH and QAlb. No support was obtained for the hypothesis that plasma levels of 27OH have a disruptive effect on the BBB. Conclusions and Implications The sex differences are discussed in relation to negative effects of 27OH on different brain functions. LINKED ARTICLES This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc
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Affiliation(s)
- Cristina Parrado-Fernandez
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden.,Discovery and Research, AlzeCure Pharma AB, Huddinge, Sweden
| | - Valerio Leoni
- Laboratory of Clinical Chemistry, Hospital of Desio, ASST-Monza and School of Medicine, University of Milano Bicocca, Monza, Italy
| | - Ahmed Saeed
- Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | | | - Anna Sandebring-Matton
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden
| | | | - Paula Bueno
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden
| | - Chaitanya Chakravarthi Gali
- Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Ute Panzenboeck
- Division of Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Angel Cedazo-Minguez
- Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden.,Rare & Neurologic Diseases Research Therapeutic Area, Neurodegeneration Research, Sanofi Pharmaceuticals, Paris, France
| | - Ingemar Björkhem
- Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
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Molina-Van den Bosch M, Jacobs-Cachá C, Vergara A, Serón D, Soler MJ. [The renin-angiotensin system and the brain]. HIPERTENSION Y RIESGO VASCULAR 2021; 38:125-132. [PMID: 33526381 DOI: 10.1016/j.hipert.2020.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/14/2020] [Accepted: 12/20/2020] [Indexed: 12/17/2022]
Abstract
The renin-angiotensin-aldosterone (RAAS) system and its effects on blood pressure and the regulation of water and electrolyte balance have been studied focusing on the cardiovascular and renal system. The activation of RAAS in other organs has local and systemic repercussions by modeling the macro- and microvasculture of peripheral organs. The brain RAAS influence on systemic blood pressure through the sympathetic nervous system. The angiotensin converting enzyme/angiotensin II/angiotensin 1 receptor axis (ACE/AngII/AT1), classical pathway, and angiotensin converting enzyme type 2/angiotensin (1-7)/Mas receptor (ACE2/Ang (1-7)/MasR), non-classical pathway, are involved in the modulation of the sympathetic response. The imbalance of these two axes with subsequently Ang II accumulation promote neurogenic hypertension and other vascular pathologies. The aminopeptidase/angiotensin IV/angiotensin 4 receptor (AMN/Ang IV/AT4) axis, which is exclusive of the brain, acts on cerebral microvasculature and participates in cognition, memory, and learning. The aim of this review is to decipher the major central RAAS mechanisms involved in blood pressure regulation. In addition, paracrine functions of brain RAAS and its role in neuroprotection and cognition are also described in this review.
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Affiliation(s)
- M Molina-Van den Bosch
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - C Jacobs-Cachá
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - A Vergara
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - D Serón
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España
| | - M J Soler
- Grup de Nefrología, Vall d'Hebron Institut de Recerca (VHIR), Servei de Nefrología, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital, Barcelona, España.
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Dai L, Zou L, Meng L, Qiang G, Yan M, Zhang Z. Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets. Mol Neurobiol 2021; 58:2183-2201. [PMID: 33411241 DOI: 10.1007/s12035-020-02232-6] [Citation(s) in RCA: 121] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 11/24/2020] [Indexed: 12/24/2022]
Abstract
Cholesterol is an indispensable component of the cell membrane and plays vital roles in critical physiological processes. Brain cholesterol accounts for a large portion of total cholesterol in the human body, and its content must be tightly regulated to ensure normal brain function. Disorders of cholesterol metabolism in the brain are linked to neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other atypical cognitive deficits that arise at old age. However, the specific role of cholesterol metabolism disorder in the pathogenesis of neurodegenerative diseases has not been fully elucidated. Statins that are a class of lipid-lowering drugs have been reported to have a positive effect on neurodegenerative diseases. Herein, we reviewed the physiological and pathological conditions of cholesterol metabolism and discussed the possible mechanisms of cholesterol metabolism and statin therapy in neurodegenerative diseases.
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Affiliation(s)
- Lijun Dai
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Li Zou
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Lanxia Meng
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Guifen Qiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, China
| | - Mingmin Yan
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Zhentao Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
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Wang T, Wang J, Hu X, Huang XJ, Chen GX. Current understanding of glucose transporter 4 expression and functional mechanisms. World J Biol Chem 2020; 11:76-98. [PMID: 33274014 PMCID: PMC7672939 DOI: 10.4331/wjbc.v11.i3.76] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/22/2020] [Accepted: 09/22/2020] [Indexed: 02/05/2023] Open
Abstract
Glucose is used aerobically and anaerobically to generate energy for cells. Glucose transporters (GLUTs) are transmembrane proteins that transport glucose across the cell membrane. Insulin promotes glucose utilization in part through promoting glucose entry into the skeletal and adipose tissues. This has been thought to be achieved through insulin-induced GLUT4 translocation from intracellular compartments to the cell membrane, which increases the overall rate of glucose flux into a cell. The insulin-induced GLUT4 translocation has been investigated extensively. Recently, significant progress has been made in our understanding of GLUT4 expression and translocation. Here, we summarized the methods and reagents used to determine the expression levels of Slc2a4 mRNA and GLUT4 protein, and GLUT4 translocation in the skeletal muscle, adipose tissues, heart and brain. Overall, a variety of methods such real-time polymerase chain reaction, immunohistochemistry, fluorescence microscopy, fusion proteins, stable cell line and transgenic animals have been used to answer particular questions related to GLUT4 system and insulin action. It seems that insulin-induced GLUT4 translocation can be observed in the heart and brain in addition to the skeletal muscle and adipocytes. Hormones other than insulin can induce GLUT4 translocation. Clearly, more studies of GLUT4 are warranted in the future to advance of our understanding of glucose homeostasis.
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Affiliation(s)
- Tiannan Wang
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Jing Wang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Xinge Hu
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
| | - Xian-Ju Huang
- College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, The University of Tennessee, Knoxville, TN 37996, United States
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Kuhla A, Meuth L, Stenzel J, Lindner T, Lappe C, Kurth J, Krause BJ, Teipel S, Glass Ä, Kundt G, Vollmar B. Longitudinal [ 18F]FDG-PET/CT analysis of the glucose metabolism in ApoE-deficient mice. EJNMMI Res 2020; 10:119. [PMID: 33029684 PMCID: PMC7541807 DOI: 10.1186/s13550-020-00711-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/24/2020] [Indexed: 11/15/2022] Open
Abstract
Background Strong line of evidence suggests that the increased risk to develop AD may at least be partly mediated by cholesterol metabolism. A key regulator of cholesterol transport is the Apolipoprotein E4 (ApoE4), which plays a fundamental role in neuronal maintenance and repair. Impaired function of ApoE4 may contribute to altered cerebral metabolism leading to higher susceptibility to neurodegeneration. Methods To determine a possible link between ApoE function and alterations in AD in the brain of Apolipoprotein E-deficient mice (ApoE−/−) in a longitudinal manner metabolic and neurochemical parameters were analyzed. Cortical metabolism was measured by 2-deoxy-2-[18F]fluoroglucose ([18F]FDG)-PET/CT and proton magnetic resonance spectroscopy (1H-MRS) served to record neurochemical status. Results By using [18F]FDG-PET/CT, we showed that brain metabolism declined significantly stronger with age in ApoE−/− versus wild type (wt) mice. This difference was particularly evident at the age of 41 weeks in almost each analyzed brain region. In contrast, the 1H-MRS-measured N-acetylaspartate to creatine ratio, a marker of neuronal viability, did not decline with age and did not differ between ApoE−/− and wt mice. Conclusion In summary, this longitudinal in vivo study shows for the first time that ApoE−/− mice depict cerebral hypometabolism without neurochemical alterations.
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Affiliation(s)
- Angela Kuhla
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057, Rostock, Germany.
| | - Lou Meuth
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057, Rostock, Germany
| | - Jan Stenzel
- Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany
| | - Tobias Lindner
- Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany
| | - Chris Lappe
- Institute of Diagnostic and Interventional Radiology, Pediatric and Neuroradiology, Rostock University Medical Center, Rostock, Germany.,German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Germany
| | - Jens Kurth
- Department of Nuclear Medicine, Rostock University Medical Center, Rostock, Germany
| | - Bernd J Krause
- Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany.,Department of Nuclear Medicine, Rostock University Medical Center, Rostock, Germany
| | - Stefan Teipel
- German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Germany.,Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
| | - Änne Glass
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Guenther Kundt
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, Rostock, Germany
| | - Brigitte Vollmar
- Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057, Rostock, Germany.,Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany
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Building GLUT4 Vesicles: CHC22 Clathrin's Human Touch. Trends Cell Biol 2020; 30:705-719. [PMID: 32620516 DOI: 10.1016/j.tcb.2020.05.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 05/24/2020] [Accepted: 05/27/2020] [Indexed: 12/18/2022]
Abstract
Insulin stimulates glucose transport by triggering regulated delivery of intracellular vesicles containing the GLUT4 glucose transporter to the plasma membrane. This process is defective in diseases such as type 2 diabetes (T2DM). While studies in rodent cells have been invaluable in understanding GLUT4 traffic, evolutionary plasticity must be considered when extrapolating these findings to humans. Recent work has identified species-specific distinctions in GLUT4 traffic, notably the participation of a novel clathrin isoform, CHC22, in humans but not rodents. Here, we discuss GLUT4 sorting in different species and how studies of CHC22 have identified new routes for GLUT4 trafficking. We further consider how different sorting-protein complexes relate to these routes and discuss other implications of these pathways in cell biology and disease.
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48
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Segarra AB, Prieto I, Banegas I, Martínez-Cañamero M, de Gasparo M, Vanderheyden P, Zorad S, Ramírez-Sánchez M. The Type of Fat in the Diet Influences the Behavior and the Relationship Between Cystinyl and Alanyl Aminopeptidase Activities in Frontal Cortex, Liver, and Plasma. Front Mol Biosci 2020; 7:94. [PMID: 32500082 PMCID: PMC7242642 DOI: 10.3389/fmolb.2020.00094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 04/22/2020] [Indexed: 12/29/2022] Open
Abstract
Insulin-regulated aminopeptidase (IRAP, cystinyl aminopeptidase, CysAP) and aminopeptidase M (alanyl aminopeptidase, AlaAP) are closely related enzymes involved in cognitive, metabolic, and cardiovascular functions. These functions may be modulated by the type of fat used in the diet. In order to analyze a possible coordinated response of both enzymes we determined simultaneously their activities in frontal cortex, liver, and plasma of adult male rats fed diets enriched with fats differing in their percentages of saturated, mono or polyunsaturated fatty acids such as sesame, sunflower, fish, olive, Iberian lard, and coconut. The systolic blood pressure, food intake, body and liver weight as well as glucose and total cholesterol levels in plasma were measured. The type of fat in the diet influences the enzymatic activities depending on the enzyme and its location. These results suggest cognitive improvement properties for diets with predominance of polyunsaturated fatty acids. Physiological parameters such as systolic blood pressure, food intake, and biochemical factors such as cholesterol and glucose in plasma were also modified depending on the type of diet, supporting beneficial properties for diets rich in mono and polyunsaturated fatty acids. Inter-tissue correlations between the analyzed parameters were also modified depending on the type of diet. If the type of fat used in the diet modifies the behavior and relationship between CysAP and AlaAP in and between frontal cortex, liver and plasma, the functions in which they are involved could also be modified.
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Affiliation(s)
| | - Isabel Prieto
- Department of Health Sciences, University of Jaen, Jaen, Spain
| | | | | | - Marc de Gasparo
- Cardiovascular & Metabolic Syndrome Adviser, Rossemaison, Switzerland
| | - Patrick Vanderheyden
- Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Stefan Zorad
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
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Porru E, Edström E, Saeed AA, Eggertsen G, Lövgren-Sandblom A, Roda A, Björkhem I. Further evidence for a continuous flux of bile acids into the brain: trapping of bile acids in subdural hematomas. Scandinavian Journal of Clinical and Laboratory Investigation 2020; 80:395-400. [PMID: 32323600 DOI: 10.1080/00365513.2020.1753108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Bile acids are known to pass the blood-brain barrier and are present at low concentrations in the brain. In a previous work, it was shown that subdural hematomas are enriched with bile acids and that the levels in such hematomas are higher than in the peripheral circulation. The mechanism behind this enrichment was never elucidated. Bile acids have a high affinity to albumin, and subdural hematomas contain almost as high albumin levels as the peripheral circulation. A subdural hematoma is encapsulated by fibrin which may allow passage of small molecules like bile acids. We hypothesized that bile acids originating from the circulation may be 'trapped' in the albumin in subdural hematomas. In the present work, we measured the conjugated and unconjugated primary bile acids cholic acid and chenodeoxycholic acid in subdural hematomas and in peripheral circulation of 24 patients. In most patients, the levels of both conjugated and free bile acids were higher in the hematomas than in the circulation, but the enrichment of unconjugated bile acids was markedly higher than that of conjugated bile acids. In patients with a known time interval between the primary bleeding and the operation, there was a correlation between this time period and the accumulation of bile acids. This relation was most obvious for unconjugated bile acids. The results are consistent with a continuous flux of bile acids, in particular unconjugated bile acids, across the blood-brain barrier. We discuss the possible physiological importance of bile acid accumulation in subdural hematomas.
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Affiliation(s)
- Emanuele Porru
- Department of Chemistry "Giacomo Ciamician", University of Bologna, Bologna, Italy
| | - Erik Edström
- Neurocentrum, Karolinska University Hospital, Solna, Sweden
| | - Ahmed A Saeed
- Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan
| | - Gösta Eggertsen
- Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden
| | | | - Aldo Roda
- Department of Chemistry "Giacomo Ciamician", University of Bologna, Bologna, Italy
| | - Ingemar Björkhem
- Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, Sweden
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50
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Merino-Serrais P, Loera-Valencia R, Rodriguez-Rodriguez P, Parrado-Fernandez C, Ismail MA, Maioli S, Matute E, Jimenez-Mateos EM, Björkhem I, DeFelipe J, Cedazo-Minguez A. 27-Hydroxycholesterol Induces Aberrant Morphology and Synaptic Dysfunction in Hippocampal Neurons. Cereb Cortex 2020; 29:429-446. [PMID: 30395175 PMCID: PMC6294414 DOI: 10.1093/cercor/bhy274] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022] Open
Abstract
Hypercholesterolemia is a risk factor for neurodegenerative diseases, but how high blood cholesterol levels are linked to neurodegeneration is still unknown. Here, we show that an excess of the blood-brain barrier permeable cholesterol metabolite 27-hydroxycholesterol (27-OH) impairs neuronal morphology and reduces hippocampal spine density and the levels of the postsynaptic protein PSD95. Dendritic spines are the main postsynaptic elements of excitatory synapses and are crucial structures for memory and cognition. Furthermore, PSD95 has an essential function for synaptic maintenance and plasticity. PSD95 synthesis is controlled by the REST-miR124a-PTBP1 axis. Here, we report that high levels of 27-OH induce REST-miR124a-PTBP1 axis dysregulation in a possible RxRγ-dependent manner, suggesting that 27-OH reduces PSD95 levels through this mechanism. Our results reveal a possible molecular link between hypercholesterolemia and neurodegeneration. We discuss the possibility that reduction of 27-OH levels could be a useful strategy for preventing memory and cognitive decline in neurodegenerative disorders.
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Affiliation(s)
- Paula Merino-Serrais
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Raul Loera-Valencia
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Patricia Rodriguez-Rodriguez
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Cristina Parrado-Fernandez
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Muhammad A Ismail
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.,Department of Neurology, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Silvia Maioli
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Eduardo Matute
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Eva Maria Jimenez-Mateos
- Department of Physiology and Medical Physics Royal, College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland
| | - Ingemar Björkhem
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Javier DeFelipe
- Laboratorio Cajal de Circuitos Corticales (CTB), Universidad Politécnica de Madrid, Madrid, Spain.,Instituto Cajal, CSIC, Madrid, Spain.,Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain
| | - Angel Cedazo-Minguez
- Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
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