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Liu M, Chen J, Sun Y. Mechanistic insights into elevated caspase-8 expression driving caspase-3 activation and Gasdermin E-dependent pyroptosis in Alzheimer's disease. Exp Cell Res 2025; 449:114594. [PMID: 40334809 DOI: 10.1016/j.yexcr.2025.114594] [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: 01/16/2025] [Revised: 04/30/2025] [Accepted: 05/03/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND This study aims to investigate the specific mechanism by which caspase-8 regulates pyroptosis through Gasdermin E (GSDME) in Alzheimer's disease (AD). By analyzing the expression level of caspase-8 in AD pathology and its impact on pyroptosis and neuroinflammation, we aim to elucidate the role of caspase-8 as a potential therapeutic target and provide new insights into the pathological research and treatment strategies for AD. METHODS We utilized GEO2R to analyze the GSE48350 and GSE118553 datasets, identifying differential genes in AD and exploring the pathways involved through GO and KEGG enrichment analyses. The expression patterns of caspase-8 in different tissues and cells were analyzed using the HPA and UCSF databases. RT-qPCR and Western blot techniques were employed to detect the expression of caspase-8 and caspase-3 in AD cellular models. By knocking down caspase-8 and caspase-3, we observed their effects on the expression of pyroptosis-related proteins and inflammatory cytokines. RESULTS This study is the first to systematically reveal that caspase-8 is significantly upregulated in AD and induces pyroptosis by activating caspase-3, which mediates GSDME cleavage. In AD cellular models, knockdown of caspase-8 resulted in significant reductions in pyroptosis and cell death. Moreover, knockdown of caspase-3 significantly decreased the cleavage of GSDME and the expression of inflammatory cytokines IL-1β and IL-18. CONCLUSION This study demonstrates that caspase-8 is significantly upregulated in Alzheimer's disease (AD) and exacerbates neuroinflammation and cell death through the activation of caspase-3 and Gasdermin E (GSDME)-dependent pyroptosis. Inhibition of caspase-8 effectively alleviates AD pathological changes, highlighting its potential as a therapeutic target.
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Affiliation(s)
- Mengzhu Liu
- The Fourth Department of Neurology, Beidahuang Group General Hospital, Harbin City, 150088, China.
| | - Jing Chen
- The Fourth Department of Neurology, Beidahuang Group General Hospital, Harbin City, 150088, China
| | - Yu Sun
- The Fourth Department of Neurology, Beidahuang Group General Hospital, Harbin City, 150088, China
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Yu Y, Lv J, Ma D, Han Y, Zhang Y, Wang S, Wang Z. Microglial ApoD-induced NLRC4 inflammasome activation promotes Alzheimer's disease progression. Animal Model Exp Med 2025; 8:773-783. [PMID: 38520135 DOI: 10.1002/ame2.12361] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/20/2023] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a progressive neurodegenerative disease with no effective therapies. It is well known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Well-balanced neuronal-microglial interactions are essential for brain functions. However, determining the role of microglia-the primary immune cells in the brain-in neuroinflammation in AD and the associated molecular basis has been challenging. METHODS Inflammatory factors in the sera of AD patients were detected and their association with microglia activation was analyzed. The mechanism for microglial inflammation was investigated. IL6 and TNF-α were found to be significantly increased in the AD stage. RESULTS Our analysis revealed that microglia were extensively activated in AD cerebra, releasing sufficient amounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, the ApoD-induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSC self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation. CONCLUSION Our studies establish the cellular basis for microglia activation in AD progression and shed light on cellular interactions important for AD treatment.
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Affiliation(s)
- Yaliang Yu
- Department of Neurology, The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, P. R. China
| | - Jianzhou Lv
- Department of Neurology, The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, P. R. China
| | - Dan Ma
- Department of Neurology, The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, P. R. China
| | - Ya Han
- Department of Neurology, The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, P. R. China
| | - Yaheng Zhang
- Department of Neurology, The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, P. R. China
| | - Shanlong Wang
- Clinical Lab, The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, P. R. China
| | - Zhitao Wang
- Department of Neurology, The Second Affiliated Hospital of Henan University of Science and Technology, Luoyang, P. R. China
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Campisciano G, Rupel K, D'Amico F, Tettamanti M, Vella F, Cason C, Comar M, Turroni S, Marcon G. Oral microbiota profile is related to cognitive status in centenarians: a clinical and biological study. Maturitas 2025; 198:108593. [PMID: 40315555 DOI: 10.1016/j.maturitas.2025.108593] [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: 09/24/2024] [Revised: 04/23/2025] [Accepted: 04/27/2025] [Indexed: 05/04/2025]
Abstract
OBJECTIVES A growing body of evidence supports the potential role of the oral microbiota in influencing cognitive function. Centenarians, at the extreme end of the lifespan, are the ideal cohort to study the long-term effects of inflammaging. STUDY DESIGN Twenty-three centenarians were examined by a neurologist, neuropsychologist and dentist to assess cognitive status and oral health. They were also profiled for oral microbiota and inflammasome. RESULTS We found less alpha diversity in the oral microbiota of participants with dementia and an overall depletion of typical oral commensals, including Alloprevotella, Prevotella, Veillonella, Fusobacterium and Leptotrichia. The latter two were also underrepresented in edentulous compared with dentate subjects. Moreover, levels of pro-inflammatory cytokines and chemokines tended to be higher in participants with dementia. CONCLUSIONS Our data support a relationship between oral microbiota, cognitive status and inflammation, which deserves further exploration to counteract cognitive decline while promoting healthy aging.
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Affiliation(s)
| | - Katia Rupel
- Department of Medical Science, University of Trieste, Trieste, Italy
| | - Federica D'Amico
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Mauro Tettamanti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Milano, Italy
| | - Filomena Vella
- ASUGI, Azienda Sanitaria Universitaria Giuliano Isontina -Trieste, Italy
| | - Carolina Cason
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - Trieste, Italy; Department of Medical Science, University of Trieste, Trieste, Italy
| | - Manola Comar
- Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - Trieste, Italy; Department of Medical Science, University of Trieste, Trieste, Italy
| | - Silvia Turroni
- Unit of Microbiome Science and Biotechnology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
| | - Gabriella Marcon
- Department of Medical Science, University of Trieste, Trieste, Italy; DMED - University of Udine, Udine, Italy
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Sun Q, Fan J, Zhao L, Qu Z, Dong Y, Wu Y, Gu S. Weizmannia coagulans BC99 Improve Cognitive Impairment Induced by Chronic Sleep Deprivation via Inhibiting the Brain and Intestine's NLRP3 Inflammasome. Foods 2025; 14:989. [PMID: 40232008 PMCID: PMC11941109 DOI: 10.3390/foods14060989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 04/16/2025] Open
Abstract
Weizmannia coagulans BC99, a Gram-positive, spore-forming, lactic acid-producing bacterium is renowned for its resilience and health-promoting properties, W. coagulans BC99 survives harsh environments, including high temperatures and gastric acidity, enabling effective delivery to the intestines. The consequences of chronic sleep deprivation (SD) include memory deficits and gastrointestinal dysfunction. In this study, a chronic sleep deprivation cognitive impairment model was established by using a sleep deprivation instrument and W. coagulans BC99 was given by gavage for 4 weeks to explore the mechanism by which BC99 improves cognitive impairment in sleep-deprived mice. BC99 improved cognitive abnormalities in novel object recognition tests induced by chronic sleep deprivation and showed behavior related to spatial memory in the Morris water maze test. W. coagulans BC99 reduced the heart mass index of sleep-deprived mice, increased the sleep-related neurotransmitters 5-HT and DA, decreased corticosterone and norepinephrine, and increased alpha diversity and community similarity. It reduced the abundance of harmful bacteria such as Olsenella, increased the abundance of beneficial bacteria such as Lactobacillus and Bifidobacterium, and promoted the production of short-chain fatty acids (SCFAs). W. coagulans BC99 also inhibits LPS translocation and the elevation of peripheral inflammatory factors by maintaining the integrity of the intestinal barrier and inhibiting the expression of the NLRP3 signaling pathway in the jejunum, thereby inhibiting the NLRP3 inflammasome in the brain of mice and reducing inflammatory factors in the brain, providing a favorable environment for the recovery of cognitive function. The present study confirmed that W. coagulans BC99 ameliorated cognitive impairment in chronic sleep-deprived mice by improving gut microbiota, especially by promoting SCFAs production and inhibiting the NLRP3 signaling pathway in the jejunum and brain. These findings may help guide the treatment of insomnia or other sleep disorders through dietary strategies.
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Affiliation(s)
- Qiaoqiao Sun
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.S.); (J.F.); (L.Z.); (Z.Q.)
| | - Jiajia Fan
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.S.); (J.F.); (L.Z.); (Z.Q.)
| | - Lina Zhao
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.S.); (J.F.); (L.Z.); (Z.Q.)
- Henan Engineering Research Center of Food Material, Henan University of Science and Technology, Luoyang 471023, China
| | - Zhen Qu
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.S.); (J.F.); (L.Z.); (Z.Q.)
| | - Yao Dong
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China;
| | - Ying Wu
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.S.); (J.F.); (L.Z.); (Z.Q.)
- Henan Engineering Research Center of Food Material, Henan University of Science and Technology, Luoyang 471023, China
| | - Shaobin Gu
- College of Food and Bioengineering, Henan University of Science and Technology, Luoyang 471000, China; (Q.S.); (J.F.); (L.Z.); (Z.Q.)
- Henan Engineering Research Center of Food Material, Henan University of Science and Technology, Luoyang 471023, China
- Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China;
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Barati N, Shojaeian A, Ramezani M, Kalhori F, Yavari Bazl MS, Zafari S, Asl SS, Motavallihaghi S. Investigating the effect of parasites (toxoplasma gondii RH strain, Leishmania major (MRHO/IR/75/ER), and hydatid cyst) antigens on Alzheimer's disease: An in vivo evaluation. Exp Neurol 2024; 377:114813. [PMID: 38735456 DOI: 10.1016/j.expneurol.2024.114813] [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: 03/07/2024] [Revised: 04/22/2024] [Accepted: 05/08/2024] [Indexed: 05/14/2024]
Abstract
This study aimed to investigate the effects of parasite antigens on Alzheimer's symptoms in animal model. Alzheimer's model was induced in Wistar rats using Amyloid-beta peptide, and treated with parasite crude antigens from T. gondii RH strain, L. major (MRHO/IR/75/ER), and HC. Spectrophotometry and real-time PCR were used to evaluate the oxidative stress levels, antioxidant enzyme activity, and gene expression of NLRP3, IL-8, IL-1β, and Caspase-1. Histological assays were performed to investigate structural changes in the hippocampus. Apoptosis was analyzed using an Annexin V Apoptosis by Flow cytometer. The levels of total oxidant, antioxidant, and SOD increased in the Alzheimer's group compared with the control group, but these factors were lower in the L. major group. The apoptosis in the treated groups was lower compared to the Alzheimer's group. IL-8 expression was significantly higher in all Alzheimer's groups, but decreased in the HC and L. major treated group compared to Alzheimer's. IL-1β and Caspase-1 expression were similarly increased in all groups compared with the control group, but decreased in the antigen-treated groups compared with Alzheimer's. NLRP3 expression was increased in all groups compared with the control group, with lower expression in HC group, but significantly decreased in L. major group compared with Alzheimer's. In histological results, only L. major group could play a therapeutic role in pathological damage of the hippocampus. The results showed that parasite antigens, specifically L. major antigens, may have neuroprotective effects that reduce oxidative stress, apoptosis, and histopathological changes in response to AD in animal model.
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Affiliation(s)
- Nastaran Barati
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Shojaeian
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mahdi Ramezani
- Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fereshte Kalhori
- Department of Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Salman Zafari
- Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Soleimani Asl
- Department of Anatomy, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Seyedmousa Motavallihaghi
- Department of Medical Parasitology and Mycology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Bai H, Zeng HM, Zhang QF, Hu YZ, Deng FF. Correlative factors of poor prognosis and abnormal cellular immune function in patients with Alzheimer's disease. World J Clin Cases 2024; 12:1063-1075. [PMID: 38464932 PMCID: PMC10921302 DOI: 10.12998/wjcc.v12.i6.1063] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/21/2023] [Accepted: 01/29/2024] [Indexed: 02/20/2024] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a serious disease causing human dementia and social problems. The quality of life and prognosis of AD patients have attracted much attention. The role of chronic immune inflammation in the pathogenesis of AD is becoming more and more important. AIM To study the relationship among cognitive dysfunction, abnormal cellular immune function, neuroimaging results and poor prognostic factors in patients. METHODS A retrospective analysis of 62 hospitalized patients clinical diagnosed with AD who were admitted to our hospital from November 2015 to November 2020. Collect cognitive dysfunction performance characteristics, laboratory test data and neuroimaging data from medical records within 24 h of admission, including Mini Mental State Examination Scale score, drawing clock test, blood T lymphocyte subsets, and neutrophils and lymphocyte ratio (NLR), disturbance of consciousness, extrapyramidal symptoms, electroencephalogram (EEG) and head nucleus magnetic spectroscopy (MRS) and other data. Multivariate logistic regression analysis was used to determine independent prognostic factors. the modified Rankin scale (mRS) was used to determine whether the prognosis was good. The correlation between drug treatment and prognostic mRS score was tested by the rank sum test. RESULTS Univariate analysis showed that abnormal cellular immune function, extrapyramidal symptoms, obvious disturbance of consciousness, abnormal EEG, increased NLR, abnormal MRS, and complicated pneumonia were related to the poor prognosis of AD patients. Multivariate logistic regression analysis showed that the decrease in the proportion of T lymphocytes in the blood after abnormal cellular immune function (odd ratio: 2.078, 95% confidence interval: 1.156-3.986, P < 0.05) was an independent risk factor for predicting the poor prognosis of AD. The number of days of donepezil treatment to improve cognitive function was negatively correlated with mRS score (r = 0.578, P < 0.05). CONCLUSION The decrease in the proportion of T lymphocytes may have predictive value for the poor prognosis of AD. It is recommended that the proportion of T lymphocytes < 55% is used as the cut-off threshold for predicting the poor prognosis of AD. The early and continuous drug treatment is associated with a good prognosis.
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Affiliation(s)
- Hua Bai
- Department of Neurology, The Third Affiliated Hospital of Guizhou Medical University in China, Duyun 558099, Guizhou Province, China
| | - Hong-Mei Zeng
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
| | - Qi-Fang Zhang
- Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang 550004, Guizhou Province, China
| | - Yue-Zhi Hu
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
| | - Fei-Fei Deng
- Department of Neurology, Guizhou Medical University, Duyun 558099, Guizhou Province, China
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Yu H, Wang F, Wu J, Gong J, Bi S, Mao Y, Jia D, Chai G. Integrated transcriptomics reveals the brain and blood biomarkers in Alzheimer's disease. CNS Neurosci Ther 2023; 29:3943-3951. [PMID: 37334737 PMCID: PMC10651972 DOI: 10.1111/cns.14316] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/20/2023] Open
Abstract
BACKGROUND The systematic molecular associations between the peripheral blood cells and brain in Alzheimer's disease (AD) remains unclear, which hinders our understanding of AD pathological mechanisms and the exploration of new diagnostic biomarkers. METHODS Here, we performed an integrated analysis of the brain and peripheral blood cells transcriptomics to establish peripheral biomarkers of AD. By employing multiple statistical analyses plus machine learning, we identified and validated multiple regulated central and peripheral network in patients with AD. RESULTS By bioinformatics analysis, a total of 243 genes were differentially expressed in the central and peripheral systems, mainly enriched in three modules: immune response, glucose metabolism and lysosome. In addition, lysosome related gene ATP6V1E1 and immune response related genes (IL2RG, OSM, EVI2B TNFRSF1A, CXCR4, STAT5A) were significantly correlated with Aβ or Tau pathology. Finally, receiver operating characteristic (ROC) analysis revealed that ATP6V1E1 showed high-diagnostic potential for AD. CONCLUSION Taken together, our data identified the main pathological pathways in AD progression, particularly the systemic dysregulation of the immune response, and provided peripheral biomarkers for AD diagnosis.
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Affiliation(s)
- Haitao Yu
- Department of Fundamental Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
| | - Fangzhou Wang
- Department of Fundamental Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
| | - Jia‐jun Wu
- Department of Fundamental Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
| | - Juan Gong
- Department of Fundamental Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
| | - Shuguang Bi
- Department of Fundamental Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
| | - Yumin Mao
- Department of Fundamental Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
| | - Dongdong Jia
- The Affiliated Mental Health Center of Jiangnan UniversityWuxi Central Rehabilitation HospitalWuxiChina
| | - Gao‐shang Chai
- Department of Fundamental Medicine, Wuxi School of MedicineJiangnan UniversityWuxiChina
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Maitre M, Jeltsch-David H, Okechukwu NG, Klein C, Patte-Mensah C, Mensah-Nyagan AG. Myelin in Alzheimer's disease: culprit or bystander? Acta Neuropathol Commun 2023; 11:56. [PMID: 37004127 PMCID: PMC10067200 DOI: 10.1186/s40478-023-01554-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals' accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αβ peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aβ peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.
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Affiliation(s)
- Michel Maitre
- Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM U1119, Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, Strasbourg, 67000, France.
| | - Hélène Jeltsch-David
- Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM U1119, Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, Strasbourg, 67000, France
- Biotechnologie et signalisation cellulaire, UMR 7242 CNRS, Université de Strasbourg, 300 Boulevard Sébastien Brant CS 10413, Illkirch cedex, 67412, France
| | - Nwife Getrude Okechukwu
- Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM U1119, Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, Strasbourg, 67000, France
| | - Christian Klein
- Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM U1119, Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, Strasbourg, 67000, France
| | - Christine Patte-Mensah
- Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM U1119, Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, Strasbourg, 67000, France
| | - Ayikoe-Guy Mensah-Nyagan
- Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM U1119, Université de Strasbourg, Bâtiment CRBS de la Faculté de Médecine, 1 rue Eugène Boeckel, Strasbourg, 67000, France
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Xia P, Ma H, Chen J, Liu Y, Cui X, Wang C, Zong S, Wang L, Liu Y, Lu Z. Differential expression of pyroptosis-related genes in the hippocampus of patients with Alzheimer's disease. BMC Med Genomics 2023; 16:56. [PMID: 36918839 PMCID: PMC10012531 DOI: 10.1186/s12920-023-01479-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 03/06/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a progressive, neurodegenerative disorder with insidious onset. Some scholars believe that there is a close relationship between pyroptosis and AD. However, studies with evidence supporting this relationship are lacking. MATERIALS AND METHODS The microarray data of AD were retrieved from the Gene Expression Omnibus (GEO) database with the datasets merged using the R package inSilicoMerging. R software package Limma was used to perform the differential expression analysis to identify the differentially expressed genes (DEGs). We further performed the enrichment analyses of the DEGs based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases to identify the metabolic pathways with a significant difference. The Gene Set Enrichment Analysis (GSEA) was applied to identify the significant pathways. The protein-protein interaction (PPI) network was constructed based on the STRING database with the hub genes identified. Quantitative real-time PCR (qRT-PCR) analyses based on HT22 cells were performed to validate the findings based on the microarray analysis. Gene expression correlation heatmaps were generated to evaluate the relationships among the genes. RESULTS A new dataset was derived by merging 4 microarray datasets in the hippocampus of AD patients in the GEO database. Differential gene expression analysis yielded a volcano plot of a total of 20 DEGs (14 up-regulated and 6 down-regulated). GO analysis revealed a group of GO terms with a significant difference, e.g., cytoplasmic vesicle membrane, vesicle membrane, and monocyte chemotaxis. KEGG analysis detected the metabolic pathways with a significant difference, e.g., Rheumatoid arthritis and Fluid shear stress and atherosclerosis. The results of the Gene Set Enrichment Analysis of the microarray data showed that gene set ALZHEIMER_DISEASE and the gene set PYROPTOSIS were both up-regulated. PPI network showed that pyroptosis-related genes were divided into two groups. In the Aβ-induced HT22 cell model, three genes (i.e., BAX, IL18, and CYCS) were revealed with significant differences. Gene expression correlation heatmaps revealed strong correlations between pyroptotic genes and AD-related genes. CONCLUSION The pyroptosis-related genes BAX, IL18, and CYCS were significantly different between AD patients and normal controls.
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Affiliation(s)
- Pengcheng Xia
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
| | - Huijun Ma
- Clinical Laboratory, Qingdao Women and Children's Hospital, Qingdao, Shandong, China
| | - Jing Chen
- Discipline of Anatomy and Pathology, Shandong First Medical University, Jinan, Shandong, China
| | - Yingchao Liu
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
| | - Xiaolin Cui
- School of Medicine, Shandong University, Jinan, Shandong, China
| | - Cuicui Wang
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
| | - Shuai Zong
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
| | - Le Wang
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China
| | - Yun Liu
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China.
| | - Zhiming Lu
- Department of Clinical Laboratory Medicine, Shandong Provincial Hospital, Shandong First Medical University, Jinan, Shandong, China.
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Dong D, Ren A, Yang Y, Su J, Liu L, Zhuo W, Liang Y. VX-765 Alleviates β-Amyloid Deposition and Secondary Degeneration in the Ipsilateral Hippocampus and Ameliorates Cognitive Decline after Focal Cortical Infarction in Rats. J Mol Neurosci 2022; 72:2389-2397. [PMID: 36441377 PMCID: PMC9805416 DOI: 10.1007/s12031-022-02088-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 11/18/2022] [Indexed: 11/29/2022]
Abstract
Focal cortical infarction leads to secondary degeneration of the ipsilateral hippocampus, which is associated with poststroke cognitive impairment. VX-765 is a potent small-molecule caspase-1 inhibitor that protects against central nervous system diseases. The present study aimed to determine the protective effects of VX-765 on β-amyloid (Aβ) deposition and secondary degeneration in the hippocampus as well as cognitive decline after cortical infarction. Sprague-Dawley rats were used to establish a distal middle cerebral artery occlusion (dMCAO) model and randomly divided into the vehicle and VX-765 groups. Rats in the vehicle and VX-765 groups, respectively, were subcutaneously injected with VX-765 (50 mg/kg/d) and an isopycnic vehicle once a day for 28 days, starting 1 h after dMCAO. At the end of this 28-day period, cognitive impairment was evaluated with the Morris water maze, and secondary hippocampal damage was evaluated with Nissl staining and immunostaining methods. Neuronal damage and pyroptosis were detected by TUNEL and immunoblotting. The results revealed that VX-765 treatment ameliorated poststroke cognitive dysfunction after ischemia. VX-765 reduced Aβ deposition, neuronal loss, and glial activation compared with the vehicle control. In addition, VX-765 treatment increased BDNF levels and normalized synaptophysin protein levels in the hippocampus after cortical infarction. Notably, VX-765 treatment significantly reduced the expression of the pyroptosis-related molecules caspase-1, NLRP3, apoptosis-associated speck-like protein (ASC), gasdermin D, IL-1β, and IL-18. Additionally, VX-765 significantly decreased the numbers of TUNEL-positive cells and the levels of Bax and cleaved caspase-3 (cC3) and enhanced the levels of Bcl-2 and Bcl-xl after ischemia. Inflammatory pathways, such as the NF-κB and mitogen-activated protein kinase (MAPK) pathways, were inhibited by VX-765 treatment after ischemia. These findings revealed that VX-765 reduced Aβ deposition, pyroptosis, and apoptosis in the ipsilateral hippocampus, which may be associated with reduced secondary degeneration and cognitive decline following focal cortical infarction.
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Affiliation(s)
- Dawei Dong
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
| | - Aihui Ren
- Department of Neurology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Ying Yang
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong, China
| | - Jiayi Su
- Department of Neurology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Libin Liu
- Department of Neurology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Wenyan Zhuo
- Department of Neurology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China
| | - Yubin Liang
- Department of Neurology, Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, China.
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11
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Wang X, Tian Y, Li C, Chen M. Exploring the key ferroptosis-related gene in the peripheral blood of patients with Alzheimer’s disease and its clinical significance. Front Aging Neurosci 2022; 14:970796. [PMID: 36118694 PMCID: PMC9475071 DOI: 10.3389/fnagi.2022.970796] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Introduction Alzheimer’s disease (AD) is the most common type of dementia, and there is growing evidence suggesting that ferroptosis is involved in its pathogenesis. In this study, we aimed to investigate the key ferroptosis-related genes in AD and identify a novel ferroptosis-related gene diagnosis model for patients with AD. Materials and methods We extracted the human blood and hippocampus gene expression data of five datasets (GSE63060, GSE63061, GSE97760, GSE48350, and GSE5281) in the Gene Expression Omnibus database as well as the ferroptosis-related genes from FerrDb. Differentially expressed ferroptosis-related genes were screened by random forest classifier, and were further used to construct a diagnostic model of AD using an artificial neural network. The patterns of immune infiltration in the peripheral immune system of AD were also investigated using the CIBERSORT algorithm. Results We first screened and identified 12 ferroptosis-related genes (ATG3, BNIP3, DDIT3, FH, GABARAPL1, MAPK14, SOCS1, SP1, STAT3, TNFAIP3, UBC, and ULK) via a random forest classifier, which was differentially expressed between the AD and normal control groups. Based on the 12 hub genes, we successfully constructed a satisfactory diagnostic model for differentiating AD patients from normal controls using an artificial neural network and validated its diagnostic efficacy in several external datasets. Further, the key ferroptosis-related genes were found to be strongly correlated to immune cells infiltration in AD. Conclusion We successfully identified 12 ferroptosis-related genes and established a novel diagnostic model of significant predictive value for AD. These results may help understand the role of ferroptosis in AD pathogenesis and provide promising therapeutic strategies for patients with AD.
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Affiliation(s)
- Xiaonan Wang
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yaotian Tian
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Chunmei Li
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Chen
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Min Chen,
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12
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Yue M, Xiao L, Yan R, Li X, Yang W. Pyroptosis in neurodegenerative diseases: What lies beneath the tip of the iceberg? Int Rev Immunol 2022:1-16. [PMID: 35312447 DOI: 10.1080/08830185.2022.2052064] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Neurodegenerative diseases gradually receive attention with a rapidly aging global population. The hallmark of them is a progressive neuronal loss in the brain or peripheral nervous system due to complex reasons ranging from protein aggregation, immune dysregulation to abnormal cell death. The death style of nerve cell is no longer restricted to apoptosis, autophagy and necrosis as confirmed before. With the successive discoveries of the gasdermin (GSDM) protein family and key caspase molecules in the past several decades, pyroptosis emerges as a novel kind of programmed cell death. A substantial body of evidence has recognized the close connection between pyroptosis and the occurrence and development of neurodegenerative diseases. In this review, we summarize molecular mechanisms of pyroptosis, evidences for pyroptosis involvement in neurodegenerative diseases and finally we hope to provide a novel angle for clinical decision-making.
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Affiliation(s)
- Mengli Yue
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Li Xiao
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Rui Yan
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Xinyi Li
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
| | - Wei Yang
- Department of Immunology, College of Basic Medical Sciences, JiLin University, Changchun City, Jilin Province, China
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13
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Wang X, Wang D, Su F, Li C, Chen M. Immune abnormalities and differential gene expression in the hippocampus and peripheral blood of patients with Alzheimer's disease. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:29. [PMID: 35282083 PMCID: PMC8848377 DOI: 10.21037/atm-21-4974] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 12/06/2021] [Indexed: 01/14/2023]
Abstract
Background Despite decades of research, no precise mechanisms of Alzheimer's disease (AD) development have been elucidated. This study aimed to investigate novel diagnostic biomarkers in both peripheral blood cells and hippocampus tissue, and the pathogenesis of memory impairment in AD. Methods mRNA microarray data, including hippocampus samples (GSE1297 and GSE5281) and peripheral blood mononuclear cells (PBMCs) (GSE63060 and GSE63061), associated with AD were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between AD and normal-aging samples were screened through a comprehensive analysis of multiple gene expression spectra after gene reannotation and batch normalization. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were used to analyze hub genes and to discover potential biomarkers related to AD. Protein-protein interaction (PPI) network maps were constructed to visualize the correlation between possible genes. The CIBERSORT algorithm was built to explore the patterns of PBMC infiltration to investigate the role of inflammation in the pathogenesis of AD. Results The bioinformatics analysis indicated 1,261 DEGs in the hippocampal samples and 290 in PBMCs when comparing patients with AD with normal-aging individuals. We selected 28 genes co-expressed in the hippocampus and PBMCs. A functional analysis of differential genes revealed that they were primarily involved in neuronal death, immune response, and mitochondrial function. Further, immune cell infiltration patterns demonstrated that the levels of naive CD4+ T cells, resting natural killer cells, M0 macrophages, and activated mast cells were higher in the peripheral blood of patients with AD, while resting memory CD4+ T cells were significantly lower. Conclusions The key gene changes present in both the hippocampus and PBMCs highly suggest their utility as an AD biomarker. In addition, according to our present results, immune abnormalities may have an important role in AD pathophysiology. When patients display these peripheral blood immune abnormalities, they may be recognized as being at high risk of developing AD.
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Affiliation(s)
- Xiaonan Wang
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Di Wang
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Su
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Chunmei Li
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Chen
- Department of Radiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.,Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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14
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Soriano-Teruel PM, García‑Laínez G, Marco-Salvador M, Pardo J, Arias M, DeFord C, Merfort I, Vicent MJ, Pelegrín P, Sancho M, Orzáez M. Identification of an ASC oligomerization inhibitor for the treatment of inflammatory diseases. Cell Death Dis 2021; 12:1155. [PMID: 34903717 PMCID: PMC8667020 DOI: 10.1038/s41419-021-04420-1] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/17/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022]
Abstract
The ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD)) protein is an scaffold component of different inflammasomes, intracellular multiprotein platforms of the innate immune system that are activated in response to pathogens or intracellular damage. The formation of ASC specks, initiated by different inflammasome receptors, promotes the recruitment and activation of procaspase-1, thereby triggering pyroptotic inflammatory cell death and pro-inflammatory cytokine release. Here we describe MM01 as the first-in-class small-molecule inhibitor of ASC that interferes with ASC speck formation. MM01 inhibition of ASC oligomerization prevents activation of procaspase-1 in vitro and inhibits the activation of different ASC-dependent inflammasomes in cell lines and primary cultures. Furthermore, MM01 inhibits inflammation in vivo in a mouse model of inflammasome-induced peritonitis. Overall, we highlight MM01 as a novel broad-spectrum inflammasome inhibitor for the potential treatment of multifactorial diseases involving the dysregulation of multiple inflammasomes.
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Affiliation(s)
- Paula M. Soriano-Teruel
- grid.418274.c0000 0004 0399 600XTargeted Therapies on Cancer and Inflammation Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain ,grid.418274.c0000 0004 0399 600XPolymer Therapeutics Lab., Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Guillermo García‑Laínez
- grid.418274.c0000 0004 0399 600XTargeted Therapies on Cancer and Inflammation Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - María Marco-Salvador
- grid.418274.c0000 0004 0399 600XTargeted Therapies on Cancer and Inflammation Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Julián Pardo
- grid.11205.370000 0001 2152 8769Centro de Investigaciones Biomédicas de Aragón (CIBA), Universidad de Zaragoza, Zaragoza, Spain
| | - Maykel Arias
- grid.11205.370000 0001 2152 8769Centro de Investigaciones Biomédicas de Aragón (CIBA), Universidad de Zaragoza, Zaragoza, Spain
| | - Christian DeFord
- grid.5963.9Department of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-Universität, Freiburg, Germany ,grid.5963.9Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-Universität, Freiburg, Germany
| | - Irmgard Merfort
- grid.5963.9Department of Pharmaceutical Biology and Biotechnology, Albert-Ludwigs-Universität, Freiburg, Germany ,grid.5963.9Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-Universität, Freiburg, Germany
| | - María J. Vicent
- grid.418274.c0000 0004 0399 600XPolymer Therapeutics Lab., Centro de Investigación Príncipe Felipe, Valencia, Spain
| | - Pablo Pelegrín
- grid.411372.20000 0001 0534 3000Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital ‘Virgen de la Arrixaca’, Murcia, Spain
| | - Mónica Sancho
- Targeted Therapies on Cancer and Inflammation Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
| | - Mar Orzáez
- Targeted Therapies on Cancer and Inflammation Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
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15
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Liu T, Wu DM, Zhang F, Zhang T, He M, Zhao YY, Li J, Li L, Xu Y. miR-142a-3p enhances FlaA N/C protection against radiation-mediated intestinal injury by modulating IRAK1/NF-κB signaling pathway. Int J Radiat Oncol Biol Phys 2021; 112:1256-1268. [PMID: 34906656 DOI: 10.1016/j.ijrobp.2021.12.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/25/2021] [Accepted: 12/02/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE To investigate the role of FlaA N/C protein-mediated pyroptosis inhibition and related miRNA in radiation protection. METHODS AND MATERIALS Mice received 10 Gy irradiation after FlaA N/C pretreatment, IRAK-1/4 Inhibitor I treatment, or PDTC treatment. Human intestinal epithelial cells (HIEC) cells received 10 Gy irradiation after FlaA N/C pretreatment, overexpressed miR-142a-3p with miR-142a-3p mimics, or inhibited miR-142a-3p with miR-142a-3p inhibitor. Mouse & Rat miRNA OneArray determined the change of relevant miRNA after FlaA N/C pretreatment, real-time PCR detected IRAK1 and miR-142a-3p expression, a CCK-8 assay evaluated cell viability, and LDH release analyzed cytotoxicity; caspase-1 activity assay, IL-1β level, and flow cytometry analyzed pyroptosis in cells; HE staining evaluated the damage of intestinal tissue; CO-IP detected the inflammation activation; immunohistochemistry, western blot analysis, and immunofluorescence analyzed activation of pyroptosis-related proteins and the activation of NF-kB signaling pathways, and Luciferase reporter assay and FISH detected the interaction between miR-142a-3p and IRAK1. RESULTS FlaA N/C reduced radiation-induced pyroptosis in vivo and in vitro, miR-142a-3p expression increased after FlaA N/C pretreatment. Up regulating the expression of miR-142a-3p inhibited radiation-induced pyroptosis in HIEC, and down regulating the expression of miR-142a-3p led to radiation-induced pyroptosis in HIEC after FlaA N/C pretreatment. IRAK1 was a direct target of miR-142a-3p and played an important role in radiation-induced pyroptosis in HIEC. Inhibiting IRAK1 reduced radiation-mediated pyroptosis in mice intestines. MiR-142a-3p down regulated IRAK1 and suppressed the NF-kB pathway. Inhibiting the NF-kB signaling pathway can reduce radiation-mediated pyroptosis in mice intestines. CONCLUSION Our findings indicated this new radioprotectant protein regulates miR-142a-3p, effectively inhibiting radiation-induced pyroptosis mediated by the IRAK1/NF-κB signaling pathway in intestinal cells.
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Affiliation(s)
- Teng Liu
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Dong-Ming Wu
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Feng Zhang
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Ting Zhang
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Miao He
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Yang-Yang Zhao
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Jin Li
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Li Li
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College
| | - Ying Xu
- School of Clinical Medicine, Chengdu Medical College; The First Affiliated Hospital of Chengdu Medical College; School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China.
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16
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Olsen I. Porphyromonas gingivalis-Induced Neuroinflammation in Alzheimer's Disease. Front Neurosci 2021; 15:691016. [PMID: 34720846 PMCID: PMC8551391 DOI: 10.3389/fnins.2021.691016] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/27/2021] [Indexed: 11/13/2022] Open
Abstract
"Chronic" periodontitis and its keystone pathogen Porphyromonas gingivalis have repeatedly been associated with Alzheimer's disease (AD). Pathological hallmarks in AD are brain accumulations of amyloid-beta and neurofibrillary tangles consisting of aggregated and hyperphosphorylated tau. In addition, neuroinflammation induced by P. gingivalis has increasingly been recognized as a factor in the pathogenesis of AD. The present mini-review discusses possible mechanisms for the induction of neuroinflammation by P. gingivalis in AD, involving factors such as pro-inflammatory mediators, amyloid-beta, tau, microglia, cathepsin B, and protein kinase R. Inflammagens of P. gingivalis such as lipopolysaccharide and gingipains are also discussed.
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Affiliation(s)
- Ingar Olsen
- Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
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17
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Han C, Hu Q, Yu A, Jiao Q, Yang Y. Mafenide derivatives inhibit neuroinflammation in Alzheimer's disease by regulating pyroptosis. J Cell Mol Med 2021; 25:10534-10542. [PMID: 34632701 PMCID: PMC8581306 DOI: 10.1111/jcmm.16984] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 09/21/2021] [Accepted: 09/24/2021] [Indexed: 11/30/2022] Open
Abstract
The main mechanism of pyroptosis is Caspase‐1–mediated GSDMD cleavage, and GSDMD is also the executive protein of pyroptosis. Our previous study has shown that mafenide can inhibit pyroptosis by inhibiting the GSDMD‐Asp275 site to suppress cleavage. In this study, sulfonamide was used as the parent nucleus structure to synthesize sulfa‐4 and sulfa‐20. Screening of drug activity in the pyroptosis model of BV2 and iBMDM cell lines revealed the efficacy of five compounds were superior to mafenide, which exerted a better inhibitory effect on the occurrence of pyroptosis. For in vivo assay, Sulfa‐4 and Sulfa‐22 were intervened in the neuroinflammation APP/PS1 mice. As a result, the administration of Sulfa‐4 and Sulfa‐22 could significantly inhibit the activation of microglia, decrease the expression of inflammatory factors in the central nervous system and simultaneously suppress the production of p30‐GSDMD as well as the expression of upstream NLRP3 inflammasome and Caspase‐1 protein. Immunoprecipitation and Biotin‐labelled assay confirmed the targeted binding relationship of Sulfa‐4 and Sulfa‐22 with GSDMD protein in the iBMDM model in vitro. In this study, we investigated a new type inhibitor of GSDMD cleavage, which exerted a good inhibitory effect on pyroptosis and provided new references for the development of inflammatory drugs in the future.
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Affiliation(s)
- Chenyang Han
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, China.,Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
| | - Qiaohong Hu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, China
| | - Anqi Yu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, China
| | - Qingcai Jiao
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, China
| | - Yi Yang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
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18
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Elwishahy A, Antia K, Bhusari S, Ilechukwu NC, Horstick O, Winkler V. Porphyromonas Gingivalis as a Risk Factor to Alzheimer's Disease: A Systematic Review. J Alzheimers Dis Rep 2021; 5:721-732. [PMID: 34755046 PMCID: PMC8543378 DOI: 10.3233/adr-200237] [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] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is a chronic neurodegenerative disease that accounts for more than 50% of all dementia cases worldwide. There is wide consensus on the risk factors of AD; however, a clear etiology remains unknown. Evidence suggests that the inflammatory-mediated disease model, such as that found with periodontal disease due to Porphyromonas gingivalis (P. gingivalis), plays a role in AD progression. OBJECTIVE This study aims to systematically review the literature on the association between P. gingivalis to AD, and to identify the homogeneity of the methods used across studies to measure P. gingivalis involvement in AD. METHODS We systematically searched studies on Cochrane library, Ovid Medline, PubMed, Web of Science, WHOLIS, Google Scholar databases, and reference lists of identified studies. RESULTS 6 studies out of 636 identified records fulfilled all eligibility criteria. Results showed no clear pathophysiology of AD due to P. gingivalis and its various virulence factors. No consensus was found in the literature pertaining to the method of measurement of AD or P. gingivalis and its virulence factors. CONCLUSION The included studies suggest that P. gingivalis bacteria play a role in the process of systemic inflammation which leads to cerebrospinal fluid inflammation and indirectly cause hastening of AD onset and progression. Our included studies revealed heterogeneity in the methodologies of measurement of AD and/or P. gingivalis and its virulence factors, which opens discussion about the benefits and weakness of possible standardization.
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Affiliation(s)
- Abdelrahman Elwishahy
- Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany
| | - Khatia Antia
- Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany
| | - Sneha Bhusari
- Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Olaf Horstick
- Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany
| | - Volker Winkler
- Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany
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19
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Heller A, Coffman SS, Jarvis K. Potentially Pathogenic Calcium Oxalate Dihydrate and Titanium Dioxide Crystals in the Alzheimer's Disease Entorhinal Cortex. J Alzheimers Dis 2021; 77:547-550. [PMID: 32804151 PMCID: PMC7592648 DOI: 10.3233/jad-200535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Knowing that Alzheimer's disease (AD) nucleates in the entorhinal cortex (EC), samples of 12 EC specimens were probed for crystals by a protocol detecting fewer than 1/5000th of those present. Of the 61 crystals found, 31 were expected and 30 were novel. Twenty-one crystals of iron oxides and 10 atherosclerosis-associated calcium pyrophosphate dihydrate crystals were expected and found. The 30 unexpected crystals were NLRP3-inflammasome activating calcium oxalate dihydrate (12) and titanium dioxide (18). Their unusual distribution raises the possibility that some were of AD origination sites.
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Affiliation(s)
- Adam Heller
- McKetta Department of Chemical Engineering and University of Texas, Austin, TX, USA
| | - Sheryl S Coffman
- McKetta Department of Chemical Engineering and University of Texas, Austin, TX, USA
| | - Karalee Jarvis
- Texas Materials Institute, University of Texas, Austin, TX, USA
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20
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Song X, Cui Z, He J, Yang T, Sun X. κ‑opioid receptor agonist, U50488H, inhibits pyroptosis through NLRP3 via the Ca 2+/CaMKII/CREB signaling pathway and improves synaptic plasticity in APP/PS1 mice. Mol Med Rep 2021; 24:529. [PMID: 34036389 PMCID: PMC8170177 DOI: 10.3892/mmr.2021.12168] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 04/09/2021] [Indexed: 01/14/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder with slow onset in most cases. Clinically, dementia associated with AD is characterized by memory disorders, aphasia, executive dysfunction and personality and behavior changes. Currently, treatment strategies attempt to reduce certain symptoms, however there is no cure for AD. The aim of the present study was to identify a novel treatment strategy for AD. Thus, the protective effects of a κ‑opioid receptor (KOR) agonist, U50488H on neural damage in AD mice were investigated. The underlying mechanism of the Ca2+/calcium/calmodulin‑dependent protein kinase II/cyclic adenosine monophosphate‑response element binding protein (Ca2+/CaMKII/CREB) signaling pathway was evaluated. Amyloid precursor protein (APP)/presenilin‑1 (PS1) mice were treated subcutaneously with a KOR agonist for 28 days. The learning and memory abilities of the APP/PS1 mice were evaluated using the Morris water maze test. Damage to hippocampal neurons was assessed using hematoxylin and eosin staining. Inflammatory factors and brain injury markers were detected using ELISA. Neurons were examined using immunofluorescence and dendritic spines were observed using Golgi‑Cox staining. Western blotting was used to detect NOD‑, LRR‑ and pyrin domain‑containing protein 3, microglial ptosis and the Ca2+/CaMKII/CREB‑related protein pathway. The KOR agonist significantly improved the brain injury observed in APP/PS1 mice, inhibited microglia pyroptosis and improved the synaptic plasticity of APP/PS1 mice, which was reversed by a KOR antagonist. Thus, the KOR agonist improved the symptoms of APP/PS1 mice by inhibiting the Ca2+/CaMKII/CREB signaling pathway.
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MESH Headings
- 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/administration & dosage
- Alzheimer Disease/metabolism
- Amyloid beta-Protein Precursor/genetics
- Amyloid beta-Protein Precursor/metabolism
- Animals
- Benzylamines/administration & dosage
- Brain Injuries/drug therapy
- Calcium/metabolism
- Calcium Signaling/drug effects
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
- Cyclic AMP Response Element-Binding Protein/metabolism
- Disease Models, Animal
- Injections, Intraperitoneal
- Injections, Subcutaneous
- Maze Learning/drug effects
- Mice, Inbred C57BL
- Mice, Transgenic
- Microglia/drug effects
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- Neuronal Plasticity/drug effects
- Presenilin-1/genetics
- Pyrolysis/drug effects
- Pyroptosis/drug effects
- Receptors, Opioid, kappa/agonists
- Sulfonamides/administration & dosage
- Mice
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Affiliation(s)
- Xiaofu Song
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
- Department of Neurology, The People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China
| | - Zhiqiang Cui
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Jiahuan He
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Tuo Yang
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
| | - Xiaohong Sun
- Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032, P.R. China
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21
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Tandon A, Singh SJ, Chaturvedi RK. Nanomedicine against Alzheimer's and Parkinson's Disease. Curr Pharm Des 2021; 27:1507-1545. [PMID: 33087025 DOI: 10.2174/1381612826666201021140904] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/06/2020] [Accepted: 08/18/2020] [Indexed: 11/22/2022]
Abstract
Alzheimer's and Parkinson's are the two most rampant neurodegenerative disorders worldwide. Existing treatments have a limited effect on the pathophysiology but are unable to fully arrest the progression of the disease. This is due to the inability of these therapeutic molecules to efficiently cross the blood-brain barrier. We discuss how nanotechnology has enabled researchers to develop novel and efficient nano-therapeutics against these diseases. The development of nanotized drug delivery systems has permitted an efficient, site-targeted, and controlled release of drugs in the brain, thereby presenting a revolutionary therapeutic approach. Nanoparticles are also being thoroughly studied and exploited for their role in the efficient and precise diagnosis of neurodegenerative conditions. We summarize the role of different nano-carriers and RNAi-conjugated nanoparticle-based therapeutics for their efficacy in pre-clinical studies. We also discuss the challenges underlying the use of nanomedicine with a focus on their route of administration, concentration, metabolism, and any toxic effects for successful therapeutics in these diseases.
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Affiliation(s)
- Ankit Tandon
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Sangh J Singh
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
| | - Rajnish K Chaturvedi
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India
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22
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Huang Y, Wang S, Huang F, Zhang Q, Qin B, Liao L, Wang M, Wan H, Yan W, Chen D, Liu F, Jiang B, Ji D, Xia X, Huang J, Xiong K. c-FLIP regulates pyroptosis in retinal neurons following oxygen-glucose deprivation/recovery via a GSDMD-mediated pathway. Ann Anat 2021; 235:151672. [PMID: 33434657 DOI: 10.1016/j.aanat.2020.151672] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 11/26/2020] [Accepted: 12/09/2020] [Indexed: 02/06/2023]
Abstract
Cellular FLICE-inhibitory protein (c-FLIP), an anti-apoptotic regulator, shows remarkable similarities to caspase-8, which plays a key role in the cleavage of gasdermin D (GSDMD). It has been reported that the oxygen-glucose deprivation/recovery (OGD/R) model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP) treatment could induce inflammation and pyroptosis. However, the regulatory role of c-FLIP in the pyroptotic death of retinal neurons is unclear. In this study, we hypothesized that c-FLIP might regulate retinal neuronal pyroptosis by GSDMD cleavage. To investigate this hypothesis, we induced retinal neuronal damage in vitro (OGD/R and LPS/ATP) and in vivo (acute high intraocular pressure [aHIOP]). Our results demonstrated that the three injuries triggered the up-regulation of pyroptosis-related proteins, and c-FLIP could cleave GSDMD to generate a functional N-terminal (NT) domain of GSDMD, causing retinal neuronal pyroptosis. In addition, c-FLIP knockdown in vivo ameliorated the already established visual impairment mediated by acute IOP elevation. Taken together, these findings revealed that decreased c-FLIP expression protected against pyroptotic death of retinal neurons possibly by inhibiting GSDMD-NT generation. Therefore, c-FLIP might provide new insights into the pathogenesis of pyroptosis-related diseases and help to elucidate new therapeutic targets and potential treatment strategies.
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Affiliation(s)
- Yanxia Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China; Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Shuchao Wang
- Center for Medical Research, The Second Xiangya Hospital of Central South University, Changsha 410013, China
| | - Fei Huang
- Center for Experimental Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Bo Qin
- Department of Anatomy, Medical College of Hubei Polytechnic University, Huang shi 435003, China
| | - Lvshuang Liao
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Mi Wang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Hao Wan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Weitao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Dan Chen
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China
| | - Fengxia Liu
- Department of Human Anatomy, School of Basic Medical Science, Xinjiang Medical University, Urumqi 830001, China
| | - Bing Jiang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha 410008, China
| | - Dan Ji
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Xiaobo Xia
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Jufang Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China.
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, China.
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23
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Hu N, Fu Y, Li WF, Yang XR, Cao M, Li FF, Chen JH, Chen XY, Zhao H, Sun ZJ, Dong DL. Chemical mitochondrial uncouplers share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation. Toxicol Appl Pharmacol 2021; 414:115426. [PMID: 33524445 DOI: 10.1016/j.taap.2021.115426] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/23/2020] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
Activation of NLRP3 inflammasome is implicated in varieties of pathologies, the aim of the present study is to characterize the effect and mechanism of mitochondrial uncouplers on NLRP3 inflammasome activation by using three types of uncouplers, niclosamide, CCCP and BAM15. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increases of NLRP3 protein and IL-1β mRNA levels in RAW264.7 macrophages and THP-1 derived macrophages. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increase of NFκB (P65) phosphorylation, and inhibited NFκB (P65) nuclear translocation in RAW264.7 macrophages. Niclosamide and BAM15 inhibited LPS-induced increase of IκBα phosphorylation in RAW264.7 macrophages, and the inhibitory effect was dependent on increased intracellular [Ca2+]i; however, CCCP showed no significant effect on IκBα phosphorylation in RAW264.7 macrophages stimulated with LPS. In conclusion, chemical mitochondrial uncouplers niclosamide, CCCP and BAM15 share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.
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Affiliation(s)
- Nan Hu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Yao Fu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Wen-Feng Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Xin-Rui Yang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Ming Cao
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Feng-Feng Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Jia-Hui Chen
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Xu-Yang Chen
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Hui Zhao
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China
| | - Zhi-Jie Sun
- Department of Pharmacology, China Pharmaceutical University, Nanjing, People's Republic of China.
| | - De-Li Dong
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin Medical University, People's Republic of China.
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24
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Olsen I. Porphyromonas Gingivalis May Seek the Alzheimer's Disease Brain to Acquire Iron from Its Surplus. J Alzheimers Dis Rep 2021; 5:79-86. [PMID: 33681719 PMCID: PMC7903007 DOI: 10.3233/adr-200272] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Iron accumulates in the brain of subjects with Alzheimer’s disease (AD). Here it promotes the aggregation of amyloid-β plaques in which it is abundant. Iron induces amyloid-β neurotoxicity by damaging free radicals and causing oxidative stress in brain areas with neurodegeneration. It can also bind to tau in AD and enhance the toxicity of tau through co-localization with neurofibrillary tangles and induce accumulation of these tangles. Porphyromonas gingivalis is a key oral pathogen in the widespread biofilm-induced disease “chronic” periodontitis, and recently, has been suggested to have an important role in the pathogenesis of AD. P. gingivalis has an obligate requirement for iron. The current paper suggests that P. gingivalis seeks the AD brain, where it has been identified, to satisfy this need. If this is correct, iron chelators binding iron could have beneficial effects in the treatment of AD. Indeed, studies from both animal AD models and humans with AD have indicated that iron chelators, e.g., lactoferrin, can have such effects. Lactoferrin can also inhibit P. gingivalis growth and proteinases and its ability to form biofilm.
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Affiliation(s)
- Ingar Olsen
- Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
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25
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Van Zeller M, Dias D, Sebastião AM, Valente CA. NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer's Disease. J Alzheimers Dis 2021; 83:939-961. [PMID: 34366341 PMCID: PMC8543248 DOI: 10.3233/jad-210268] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2021] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.
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Affiliation(s)
- Mariana Van Zeller
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Diogo Dias
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ana M. Sebastião
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia A. Valente
- Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
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26
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Yang L, Liu Y, Wang Y, Li J, Liu N. Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway. Clinics (Sao Paulo) 2021; 76:e2348. [PMID: 33681944 PMCID: PMC7920406 DOI: 10.6061/clinics/2021/e2348] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/05/2020] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVES TTP488, an antagonist of the receptor for advanced glycation end-products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). However, the mechanism underlying the protective action of TTP488 against AD has not yet been fully explored. METHODS Healthy male rats were exposed to aberrant amyloid β (Aβ) 1-42. Lipopolysaccharide (LPS) and the NOD-like receptor family pyrin domain containing 1 (NLRP1) overexpression lentivirus were injected to activate the NLRP1 inflammasome and exacerbate AD. TTP488 was administered to reverse AD injury. Finally, tofacitinib and fludarabine were used to inhibit the activity of Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) to prove the relationship between the JAK/STAT signaling pathway and TTP488. RESULTS LPS and NLRP1 overexpression significantly increased the NLRP1 levels, reduced neurological function, and aggravated neuronal damage, as demonstrated by the impact latency time of, time spent by, and length of the platform covered by, the mice in the Morris water maze assay, Nissl staining, and immunofluorescence staining in rats with AD. CONCLUSIONS TTP488 administration successfully reduced AD injury and reversed the aforementioned processes. Additionally, tofacitinib and fludarabine administration could further reverse AD injury after the TTP488 intervention. These results suggest a new potential mechanism underlying the TTP488-mediated alleviation of AD injury.
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Affiliation(s)
- Lijuan Yang
- Nursing Faculty of Xingtai Medical College, Xingtai, Hebei 054008, China
| | - Yepei Liu
- Medical Image Center, Xingtai City Fifth Hospital, Xingtai, Hebei 054008, China
| | - Yuanyuan Wang
- Nursing Faculty of Xingtai Medical College, Xingtai, Hebei 054008, China
| | - Junsheng Li
- Nursing Faculty of Xingtai Medical College, Xingtai, Hebei 054008, China
- *Corresponding authors. E-mails: /
| | - Na Liu
- Nursing Faculty of Xingtai Medical College, Xingtai, Hebei 054008, China
- *Corresponding authors. E-mails: /
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27
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Yu J, Zhu H, Taheri S, Mondy W, Perry S, Kirstein C, Kindy MS. Effects of GrandFusion Diet on Cognitive Impairment in Transgenic Mouse Model of Alzheimer's Disease. Nutrients 2020; 13:nu13010117. [PMID: 33396967 PMCID: PMC7824640 DOI: 10.3390/nu13010117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/26/2020] [Accepted: 12/27/2020] [Indexed: 12/17/2022] Open
Abstract
Alzheimer’s disease (AD) is the result of the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. At the present time, there are no possible treatments for the disease. We have recently shown that diets enriched in phytonutrients show protection or limit the extent of damage in a number of neurological disorders. GrandFusion (GF) diets have attenuated the outcomes in animal models of traumatic brain injury, cerebral ischemia, and chronic traumatic encephalopathy. In this study, we investigated the effect of GF diets in a mouse model of AD prior to the development of amyloid plaques to show how this treatment paradigm would alter the accumulation of Aβ peptide and related pathologic changes (i.e., inflammation, cathepsin B, and memory impairment). Administration of GF diets (2–4%) over a period of four months in APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of amyloid load, and inflammation, increased cathepsin B expression, and improved spatial orientation. Additionally, treatment with GF diets increased nerve growth factor (NGF) levels in the brain and tempered the memory impairment in the animal model. These data suggest that GF diets may alter the development and progression of the mechanisms associated with the disease process to effectively modify AD pathogenesis.
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Affiliation(s)
- Jin Yu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.Y.); (H.Z.); (S.T.); (W.M.)
| | - Hong Zhu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.Y.); (H.Z.); (S.T.); (W.M.)
| | - Saeid Taheri
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.Y.); (H.Z.); (S.T.); (W.M.)
| | - William Mondy
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.Y.); (H.Z.); (S.T.); (W.M.)
| | | | - Cheryl Kirstein
- Department of Psychology, College of Arts and Sciences, University of South Florida, Tampa, FL 33620, USA;
| | - Mark S. Kindy
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33620, USA; (J.Y.); (H.Z.); (S.T.); (W.M.)
- Department of Psychology, College of Arts and Sciences, University of South Florida, Tampa, FL 33620, USA;
- James A. Haley Veterans Administration Medical Center, Research, Tampa, FL 33612, USA
- Shriners Hospital for Children, Research, Tampa, FL 33612, USA
- Correspondence: ; Tel.: +1-813-974-1468
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28
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Valenzuela PL, Castillo-García A, Morales JS, de la Villa P, Hampel H, Emanuele E, Lista S, Lucia A. Exercise benefits on Alzheimer's disease: State-of-the-science. Ageing Res Rev 2020; 62:101108. [PMID: 32561386 DOI: 10.1016/j.arr.2020.101108] [Citation(s) in RCA: 197] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 05/29/2020] [Accepted: 06/06/2020] [Indexed: 01/15/2023]
Abstract
Although there is no unanimity, growing evidence supports the value of regular physical exercise to prevent Alzheimer's disease as well as cognitive decline in affected patients. Together with an introductory summary on epidemiological evidence, the aim of this review is to summarize the current knowledge on the potential biological mechanisms underlying exercise benefits in this condition. Regular physical exercise has proven to be beneficial for traditional cardiovascular risk factors (e.g., reduced vascular flow, diabetes) involved in the pathogenesis of Alzheimer's disease. Exercise also promotes neurogenesis via increases in exercise-induced metabolic factors (e.g., ketone bodies, lactate) and muscle-derived myokines (cathepsin-B, irisin), which in turn stimulate the production of neurotrophins such as brain-derived neurotrophic factor. Finally, regular exercise exerts anti-inflammatory effects and improves the brain redox status, thereby ameliorating the pathophysiological hallmarks of Alzheimer's disease (e.g., amyloid-β deposition). In summary, physical exercise might provide numerous benefits through different pathways that might, in turn, help prevent risk and progression of Alzheimer's disease. More evidence is needed, however, based on human studies.
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29
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PM2.5 compromises antiviral immunity in influenza infection by inhibiting activation of NLRP3 inflammasome and expression of interferon-β. Mol Immunol 2020; 125:178-186. [PMID: 32717666 DOI: 10.1016/j.molimm.2020.07.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 06/26/2020] [Accepted: 07/01/2020] [Indexed: 01/17/2023]
Abstract
PM2.5, a major component of air pollutants, has caused severe health problems. It has been reported that PM2.5 index is closely associated with severity of influenza A virus (IAV) infection. However, the underlying mechanisms have not been addressed. NLRP3 inflammasome and type I interferon signaling regulate host defense against influenza infection. The present study investigated the potential effects of air pollutants on host defense against influenza infection in vitro and in vivo. In this study, different concentrations of PM2.5 were pre-exposed to macrophages and mice before IAV infection to assess the negative effects of air pollutants in virus infection. We found that exposure to PM2.5 deteriorated influenza virus infection via compromising innate immune responses manifested by a decrease IL-1β and IFN-β production in vitro. Meanwhile, mice exposed with PM2.5 were susceptible to PR8 virus infection due to down-regulation of IL-1β and IFN-β. Mechanistically, PM 2.5 exposure suppressed the NLRP3 inflammasome activation and the AHR-TIPARP signaling pathway, by which compromised the anti-influenza immunity. Thus, our study revealed that PM2.5 could alter macrophage inflammatory responses by suppressing LPS-induced activation of NLRP3 inflammasome and expression of IFN-β during influenza infection. These findings provided us new insights in understanding that PM2.5 combining with influenza infection could enhance the severity of pneumonia.
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30
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Mészáros Á, Molnár K, Nógrádi B, Hernádi Z, Nyúl-Tóth Á, Wilhelm I, Krizbai IA. Neurovascular Inflammaging in Health and Disease. Cells 2020; 9:cells9071614. [PMID: 32635451 PMCID: PMC7407516 DOI: 10.3390/cells9071614] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/02/2020] [Indexed: 12/19/2022] Open
Abstract
Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.
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Affiliation(s)
- Ádám Mészáros
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Doctoral School of Biology, University of Szeged, 6726 Szeged, Hungary
| | - Kinga Molnár
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Theoretical Medicine Doctoral School, University of Szeged, 6720 Szeged, Hungary
| | - Bernát Nógrádi
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Foundation for the Future of Biomedical Sciences in Szeged, Szeged Scientists Academy, 6720 Szeged, Hungary
| | - Zsófia Hernádi
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Foundation for the Future of Biomedical Sciences in Szeged, Szeged Scientists Academy, 6720 Szeged, Hungary
| | - Ádám Nyúl-Tóth
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Imola Wilhelm
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310414 Arad, Romania
| | - István A. Krizbai
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary; (Á.M.); (K.M.); (B.N.); (Z.H.); (Á.N.-T.); (I.W.)
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310414 Arad, Romania
- Correspondence: ; Tel.: +36-62-599-794
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Wong MY, Lewis M, Doherty JJ, Shi Y, Cashikar AG, Amelianchik A, Tymchuk S, Sullivan PM, Qian M, Covey DF, Petsko GA, Holtzman DM, Paul SM, Luo W. 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner. J Neuroinflammation 2020; 17:192. [PMID: 32552741 PMCID: PMC7298825 DOI: 10.1186/s12974-020-01869-3] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 06/08/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models. METHODS We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry. RESULTS We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity. CONCLUSION 25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.
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Affiliation(s)
- Man Ying Wong
- grid.5386.8000000041936877XAppel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
| | - Michael Lewis
- grid.476678.c0000 0004 5913 664XSage Therapeutics, Cambridge, Massachusetts USA
| | - James J. Doherty
- grid.476678.c0000 0004 5913 664XSage Therapeutics, Cambridge, Massachusetts USA
| | - Yang Shi
- grid.4367.60000 0001 2355 7002Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO USA
| | - Anil G. Cashikar
- grid.4367.60000 0001 2355 7002Departments of Neurology and Psychiatry, Hope Center for Neurological Disorders, Taylor Family Institute, Washington University School of Medicine, St. Louis, MO USA
| | - Anna Amelianchik
- grid.5386.8000000041936877XAppel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
| | - Svitlana Tymchuk
- grid.5386.8000000041936877XAppel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
| | - Patrick M. Sullivan
- grid.281208.10000 0004 0419 3073Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center’s Geriatric Research, Education and Clinical Center, Durham, NC USA
| | - Mingxing Qian
- grid.4367.60000 0001 2355 7002Departments of Developmental Biology, Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110 USA
| | - Douglas F. Covey
- grid.4367.60000 0001 2355 7002Departments of Developmental Biology, Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63110 USA
| | - Gregory A. Petsko
- grid.5386.8000000041936877XAppel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY USA
| | - David M. Holtzman
- grid.4367.60000 0001 2355 7002Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO USA
| | - Steven M. Paul
- grid.476678.c0000 0004 5913 664XSage Therapeutics, Cambridge, Massachusetts USA ,grid.4367.60000 0001 2355 7002Departments of Neurology and Psychiatry, Hope Center for Neurological Disorders, Taylor Family Institute, Washington University School of Medicine, St. Louis, MO USA
| | - Wenjie Luo
- Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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Gao Z, Sui J, Fan R, Qu W, Dong X, Sun D. Emodin Protects Against Acute Pancreatitis-Associated Lung Injury by Inhibiting NLPR3 Inflammasome Activation via Nrf2/HO-1 Signaling. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1971-1982. [PMID: 32546964 PMCID: PMC7247729 DOI: 10.2147/dddt.s247103] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022]
Abstract
Aim Lung injury is a common complication of acute pancreatitis (AP), which leads to the development of acute respiratory distress syndrome and causes high mortality. In the present study, we investigated the therapeutic effect of emodin on AP-induced lung injury and explored the molecular mechanisms involved. Materials and Methods Thirty male Sprague-Dawley rats were randomly divided into AP (n=24) and normal (n=6) groups. Rats in the AP group received a retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and then randomly assigned to untreated, emodin, combined emodin and ML385, and dexamethasone (DEX) groups. Pancreatic and pulmonary injury was assessed using H&E staining. In in vitro study, rat alveolar epithelial cell line L2 cells were exposed to lipopolysaccharide and treated with emodin. Nrf2 siRNA pool was applied for the knockdown of Nrf2. The contents of the pro-inflammatory cytokines in the bronchoalveolar lavage fluid and lung were determined using enzyme-linked immunosorbent assay. The expressions of related mRNAs and proteins in the lung or L2 cells were detected using real-time polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence. Key Findings Emodin administration alleviated pancreatic and pulmonary injury of rats with AP. Emodin administration suppressed the production of proinflammatory cytokines, downregulated NLRP3, ASC and caspase-1 expressions and inhibited NF-κB nuclear accumulation in the lung. In addition, Emodin increased Nrf2 nuclear translocation and upregulated HO-1 expression. Moreover, the anti-inflammatory effect of emodin was blocked by Nrf2 inhibitor ML385. Conclusion Emodin effectively protects rats against AP-associated lung injury by inhibiting NLRP3 inflammasome activation via Nrf2/HO-1 signaling.
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Affiliation(s)
- Zhenming Gao
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People's Republic of China
| | - Jidong Sui
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People's Republic of China
| | - Rong Fan
- Department of International Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People's Republic of China
| | - Weikun Qu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People's Republic of China
| | - Xuepeng Dong
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People's Republic of China
| | - Deguang Sun
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People's Republic of China
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Lin JW, Chang CH, Caffrey JL. Examining the association between oral health status and dementia: A nationwide nested case-controlled study. Exp Biol Med (Maywood) 2020; 245:231-244. [PMID: 32039633 DOI: 10.1177/1535370220904924] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Alzheimer’s disease as a consequence of chronic brain inflammation mediated by infectious microbes including the oral microbiome continues to attract support. Taiwan’s National Insurance database was used to evaluate associations between dental health and Alzheimer’s disease; 209,112 new cases of Alzheimer’s disease were matched 1:4 with 836,448 dementia-free controls to test the hypothesis that better dental health would be associated with less occurrence of dementia. Ten year dental records and conditional logistic regression models were used to estimate the odds ratios associated with Alzheimer’s disease. Subgroup analyses compared vascular Alzheimer’s disease and sporadic Alzheimer’s disease. As the population aged, Alzheimer’s disease diagnoses were more frequent with a 10 fold upward inflection after 60. Nearly 56% of sporadic Alzheimer’s disease patients were women but less than 50% had vascular Alzheimer’s disease. Comorbidities were 10–20% higher in the Alzheimer’s disease patients than in controls, but stroke, chronic infection, and pneumonia were 40–45% more common in the vascular Alzheimer’s disease patients. Heart disease, hypertension, diabetes, stroke, peripheral artery disease, pneumonia, and herpetic disease (HSV) were all associated with higher odds of Alzheimer’s disease. HSV was not a factor in the vascular Alzheimer’s disease. Routine dental procedures tended to lower odds ratios. Root canals and extractions that restore oral homeostasis were associated with lower odds of dementia. However, when extractions exceeded four, the odds of Alzheimer’s disease rose. The fact that Alzheimer’s disease was not associated with periodontal procedures per se but with more frequent periodontal emergencies suggested again a chronic issue. Dental health costs suggest that good dental care was associated with lower odds of Alzheimer’s disease except for radiographic costs which were consistently associated with higher odds, independent of oral health. Common comorbid conditions were associated with higher odds of Alzheimer’s disease and oral health care was associated with lower odds, providing support for the hypothesis that the oral microbiome is a factor in the development of Alzheimer’s disease. Impact statement This study clearly demonstrates the power and value of a nationally applied digital medical record. Longitudinal studies of gradually developing pathologies like dementia have often been limited by sample size and narrow and incomplete medical histories. The Taiwan National Insurance database provides an unparalleled opportunity for detailed analyses of associations between current medical conditions and a spectrum of prior medical and dental events. The temporal impact of the database will only become more important as the past historical record progressively expands going forward. The inclusion of dental records in assessing the relationship with subsequent dementia is very important because this information is often unavailable or dependent on subject recall. This study clearly establishes associations between a variety of suspected cardiovascular and metabolic factors and the odds of dementia. A critical outcome should include the design of targeted interventions and the subsequent assessment of their efficacy.
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Affiliation(s)
- J W Lin
- Cardiovascular Center, National Taiwan University Hospital Yunlin Branch, Douliu City, Yunlin County 64051
| | - C H Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 10617
| | - J L Caffrey
- Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, TX 76107, USA
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Li Y, Xu P, Shan J, Sun W, Ji X, Chi T, Liu P, Zou L. Interaction between hyperphosphorylated tau and pyroptosis in forskolin and streptozotocin induced AD models. Biomed Pharmacother 2020; 121:109618. [DOI: 10.1016/j.biopha.2019.109618] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/17/2019] [Accepted: 10/26/2019] [Indexed: 12/15/2022] Open
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Zhong X, Liu M, Yao W, Du K, He M, Jin X, Jiao L, Ma G, Wei B, Wei M. Epigallocatechin-3-Gallate Attenuates Microglial Inflammation and Neurotoxicity by Suppressing the Activation of Canonical and Noncanonical Inflammasome via TLR4/NF-κB Pathway. Mol Nutr Food Res 2019; 63:e1801230. [PMID: 31374144 DOI: 10.1002/mnfr.201801230] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 06/30/2019] [Indexed: 01/09/2023]
Abstract
SCOPE In this study, it has been investigated whether the neuroprotective efficacy of epigallocatechin-3-gallate (EGCG) is mediated by inhibition of canonical and noncanonical inflammasome activation via toll-like receptor 4 (TLR4)/NF-κB pathway both in LPS+Aβ-induced microglia in vitro and in APP/PS1 mice in vivo. METHODS AND RESULTS In BV2 cells, EGCG inhibits the expressions of Iba-1, cleaved IL-1β, and cleaved IL-18 induced by LPS+Aβ. Then, the supernatants are used to treat SH-SY5Y cells, and EGCG treatment significantly recovers the neurotoxicity from LPS+Aβ-induced microglial conditioned media. Subsequently, it has been found that EGCG reduces the microglial expressions of caspase-1 p20, NLRP3, and caspase-11 p26. Furthermore, the expression levels of Toll-like receptor 4 (TLR4), p-IKK/IKK, and p-NF-κB/NF-κB were decreased after EGCG treatment. As expected, when a caspase-1 specific inhibitor Z-YVAD-FMK, and an IKK and caspase-11 inhibitor wedelolactone are used for blocking, Z-YVAD-FMK and wedelolactone exacerbate the inhibitory efficacy than using EGCG alone. Finally, consistent with the results obtained in BV2 cells, EGCG treatment reduces microglial inflammation and neurotoxicity by suppressing the activation of canonical NLRP3 and noncanonical caspase-11-dependent inflammasome via TLR4/NF-κB pathway in LPS+Aβ-induced rat primary microglia and hippocampus of APP/PS1 mice. CONCLUSION EGCG attenuates microglial inflammation and neurotoxicity by inhibition of canonical NLRP3 and noncanonical caspase-11-dependent inflammasome activation via TLR4/NF-κB pathway.
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Affiliation(s)
- Xin Zhong
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Mingyan Liu
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Weifan Yao
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Ke Du
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Miao He
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Xin Jin
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Linchi Jiao
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Guowei Ma
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Binbin Wei
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
| | - Minjie Wei
- School of Pharmacy, Department of Pharmacology, China Medical University, Shenyang, 110122, China.,Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, Shenyang, 110122, China
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Poor Oral Health and Its Neurological Consequences: Mechanisms of Porphyromonas gingivalis Involvement in Cognitive Dysfunction. ACTA ACUST UNITED AC 2019. [DOI: 10.1007/s40496-019-0212-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Chen S, Zhou C, Yu H, Tao L, An Y, Zhang X, Wang Y, Wang Y, Xiao R. 27-Hydroxycholesterol Contributes to Lysosomal Membrane Permeabilization-Mediated Pyroptosis in Co-cultured SH-SY5Y Cells and C6 Cells. Front Mol Neurosci 2019; 12:14. [PMID: 30881285 PMCID: PMC6405519 DOI: 10.3389/fnmol.2019.00014] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/15/2019] [Indexed: 01/01/2023] Open
Abstract
Purpose: Emerging evidence suggests that 27-Hydroxycholesterol (27-OHC) causes neurodegenerative diseases through the induction of cytotoxicity and cholesterol metabolism disorder. The objective of this study is to determine the impacts of 27-OHC on lysosomal membrane permeabilization (LMP) and pyroptosis in neurons in the development of neural degenerative diseases. Methods: In this study, SH-SY5Y cells and C6 cells were co-cultured in vitro to investigate the influence of 27-OHC on the function of lysosome, LMP and pyroptosis related factors in neuron. Lyso Tracker Red (LTR) was used to detect the changes of lysosome pH, volume and number. Acridine orange (AO) staining was also used to detect the LMP in neurons. Then the morphological changes of cells were observed by a scanning electron microscope (SEM). The content of lysosome function associated proteins [including Cathepsin B (CTSB), Cathepsin D (CTSD), lysosomal-associated membraneprotein-1 (LAMP-1), LAMP-2] and the pyroptosis associated proteins [including nod-like recepto P3 (NLRP3), gasdermin D (GSDMD), caspase-1 and interleukin (IL)-1β] were detected through Western blot. Results: Results showed higher levels of lysosome function associated proteins, such as CTSB (p < 0.05), CTSD (p < 0.05), LAMP-1 (p < 0.01), LAMP-2; p < 0.01) in 27-OHC treated group than that in the control group. AO staining and LTR staining showed that 27-OHC induced lysosome dysfunction with LMP. Content of pyroptosis related factor proteins, such as GSDMD (p < 0.01), NLRP3 (p < 0.001), caspase-1 (p < 0.01) and IL-1β (p < 0.01) were increased in 27-OHC treated neurons. Additionally, CTSB was leaked through LMP into the cytosol and induced pyroptosis. Results from the present study also suggested that the CTSB is involved in activation of pyroptosis. Conclusion: Our data indicate that 27-OHC contributes to the pathogenesis of cell death by inducing LMP and pyroptosis in neurons.
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Affiliation(s)
- Si Chen
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Cui Zhou
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Huiyan Yu
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Lingwei Tao
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Yu An
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Xiaona Zhang
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Ying Wang
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Yushan Wang
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
| | - Rong Xiao
- Beijing Key Laboratory of Environmental Toxicology, School of Public Health, Capital Medical University, Beijing, China
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Differential Expression of mRNAs in the Brain Tissues of Patients with Alzheimer's Disease Based on GEO Expression Profile and Its Clinical Significance. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8179145. [PMID: 30918899 PMCID: PMC6413412 DOI: 10.1155/2019/8179145] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 12/28/2018] [Accepted: 02/04/2019] [Indexed: 12/18/2022]
Abstract
Background Early diagnosis of Alzheimer's disease (AD) is an urgent point for AD prevention and treatment. The biomarkers of AD still remain indefinite. Based on the bioinformatics analysis of mRNA differential expressions in the brain tissues and the peripheral blood samples of Alzheimer's disease (AD) patients, we investigated the target mRNAs that could be used as an AD biomarker and developed a new effective, practical clinical examination program. Methods We compared the AD peripheral blood mononuclear cells (PBMCs) expression dataset (GEO accession GSE4226 and GSE18309) with AD brain tissue expression datasets (GEO accessions GSE1297 and GSE5281) from GEO in the present study. The GEO gene database was used to download the appropriate gene expression profiles to analyze the differential mRNA expressions between brain tissue and blood of AD patients and normal elderly. The Venn diagram was used to screen out the differential expression of mRNAs between the brain tissue and blood. The protein-protein interaction network map (PPI) was used to view the correlation between the possible genes. GO (gene ontology) and KEGG (Kyoto Gene and Genomic Encyclopedia) were used for gene enrichment analysis to determine the major affected genes and the function or pathway. Results Bioinformatics analysis revealed that there were differentially expressed genes in peripheral blood and hippocampus of AD patients. There were 4958 differential mRNAs in GSE18309, 577 differential mRNAs in GSE4226 in AD PBMCs sample, 7464 differential mRNAs in GSE5281, and 317 differential mRNAs in GSE129 in AD brain tissues, when comparing between AD patients and healthy elderly. Two mRNAs of RAB7A and ITGB1 coexpressed in hippocampus and peripheral blood were screened. Furthermore, functions of differential genes were enriched by the PPI network map, GO, and KEGG analysis, and finally the chemotaxis, adhesion, and inflammatory reactions were found out, respectively. Conclusions ITGB1 and RAB7A mRNA expressions were both changed in hippocampus and PBMCs, highly suggested being used as an AD biomarker with AD. Also, according to the results of this analysis, it is indicated that we can test the blood routine of the elderly for 2-3 years at a frequency of 6 months or one year. When a patient continuously detects the inflammatory manifestations, it is indicated as a potentially high-risk AD patient for AD prevention.
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GM6 Attenuates Alzheimer's Disease Pathology in APP Mice. Mol Neurobiol 2019; 56:6386-6396. [PMID: 30798443 DOI: 10.1007/s12035-019-1517-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 01/29/2019] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) results in the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. Regardless of whether or not these entities are a cause or consequence of the disease process, preventing their accumulation or accelerating their clearance may slow the rate of AD onset. Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. GM6 is a six-amino-acid component of MNTF that appears to replicate its activity spectrum. In this study, we investigated the effect of GM6 in a mouse model of AD before the development of amyloid plaques and determined how this treatment affected the accumulation of Aβ peptide and related pathologic changes (e.g., inflammation, nerve growth factor (NGF) expression, cathepsin B, and memory impairment). Application of GM6 over a 4-month period in young APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of inflammation and amyloid load, increased cathepsin B expression, and improved spatial orientation. In addition, treatment with GM6 increased brain NGF levels and tempered memory impairment by ∼ 50% at the highest dose. These data suggest that GM6 may modulate disease-determining pathways at an early stage to slow the histological and clinical progression of AD.
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Zheng H, Cheng B, Li Y, Li X, Chen X, Zhang YW. TREM2 in Alzheimer's Disease: Microglial Survival and Energy Metabolism. Front Aging Neurosci 2018; 10:395. [PMID: 30532704 PMCID: PMC6265312 DOI: 10.3389/fnagi.2018.00395] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/13/2018] [Indexed: 12/16/2022] Open
Abstract
Alzheimer’s disease (AD) is the leading cause of age-related dementia among the elderly population. Recent genetic studies have identified rare variants of the gene encoding the triggering receptor expressed on myeloid cells-2 (TREM2) as significant genetic risk factors in late-onset AD (LOAD). TREM2 is specifically expressed in brain microglia and modulates microglial functions in response to key AD pathologies such as amyloid-β (Aβ) plaques and tau tangles. In this review article, we discuss recent research progress in our understanding on the role of TREM2 in microglia and its relevance to AD pathologies. In addition, we discuss evidence describing new TREM2 ligands and the role of TREM2 signaling in microglial survival and energy metabolism. A comprehensive understanding of TREM2 function in the pathogenesis of AD offers a unique opportunity to explore the potential of this microglial receptor as an alternative target in AD therapy.
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Affiliation(s)
- Honghua Zheng
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China.,Shenzhen Research Institute, Xiamen University, Shenzhen, China
| | - Baoying Cheng
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China
| | - Yanfang Li
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China.,Shenzhen Research Institute, Xiamen University, Shenzhen, China
| | - Xin Li
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China
| | - Xiaofen Chen
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China.,Shenzhen Research Institute, Xiamen University, Shenzhen, China
| | - Yun-Wu Zhang
- Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China
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41
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Gu QF, Yu JZ, Wu H, Li YH, Liu CY, Feng L, Zhang GX, Xiao BG, Ma CG. Therapeutic effect of Rho kinase inhibitor FSD-C10 in a mouse model of Alzheimer's disease. Exp Ther Med 2018; 16:3929-3938. [PMID: 30344671 PMCID: PMC6176147 DOI: 10.3892/etm.2018.6701] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 08/23/2018] [Indexed: 12/29/2022] Open
Abstract
Fasudil, a Rho kinase (ROCK) inhibitor, effectively inhibits disease severity in a mouse model of Alzheimer's disease (AD). However, given its significant limitations, including a relatively narrow safety window and poor oral bioavailability, Fasudil is not suitable for long-term use. Thus, screening for ROCK inhibitor(s) that are more efficient, safer, can be used orally and suitable for long-term use in the treatment of neurodegenerative disorders is required. The main purpose of the present study is to explore whether FSD-C10, a novel ROCK inhibitor, has therapeutic potential in amyloid precursor protein/presenilin-1 transgenic (APP/PS1 Tg) mice, and to determine possible mechanisms of its action. The results showed that FSD-C10 effectively improved learning and memory impairment, accompanied by reduced expression of amyloid-β 1-42 (Aβ1-42), Tau protein phosphorylation (P-tau) and β-site APP-cleaving enzyme in the hippocampus and cortex area of brain. In addition, FSD-C10 administration boosted the expression of synapse-associated proteins, such as postynaptic density protein 95, synaptophsin, α-amino 3-hydroxy-5-methyl-4-isoxa-zolep-propionate receptor and neurotrophic factors, e,g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Taken together, our results demonstrate that FSD-C10 has therapeutic potential in the AD mouse model, possibly through inhibiting the formation of Aβ1-42 and P-tau, and promoting the generation of synapse-associated proteins and neurotrophic factors.
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Affiliation(s)
- Qing-Fang Gu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Jie-Zhong Yu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Hao Wu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Yan-Hua Li
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Chun-Yun Liu
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Ling Feng
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China
| | - Guang-Xian Zhang
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Bao-Guo Xiao
- Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200025, P.R. China
| | - Cun-Gen Ma
- Department of Neurology, Institute of Brain Science, Medical School, Shanxi Datong University, Datong, Shanxi 037009, P.R. China.,2011 Collaborative Innovation Center/Research Center of Neurobiology, Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi 030024, P.R. China
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42
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García-Laínez G, Sancho M, García-Bayarri V, Orzáez M. Identification and validation of uterine stimulant methylergometrine as a potential inhibitor of caspase-1 activation. Apoptosis 2018; 22:1310-1318. [PMID: 28755170 PMCID: PMC5630661 DOI: 10.1007/s10495-017-1405-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Inflammasomes are intracellular multiprotein complexes of the innate immune system. Upon an inflammatory insult, such as infection or intracellular damage, a nucleotide-binding oligomerization domain-like receptor (NLR) sensor protein and the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) are assembled to activate protease procaspase-1. This protease processes pro-IL-1β and pro-IL-18 cytokines, which are released to induce the inflammatory response. De-regulation of inflammasome contributes to the progression of several diseases, such as Alzheimer’s disease, diabetes, cancer, inflammatory and autoimmune disorders. We herein describe the identification of methylergometrine (MEM), a drug currently used as a smooth muscle constrictor during postpartum hemorrhage, as an inhibitor of the inflammasome complex in ASC-mediated procaspase-1 activation screening. MEM inhibits the activation of the nucleotide-binding oligomerization domain-like receptor protein 1 (NLRP1) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes in cellular models upon different pro-inflammatory stimuli. Our results suggest that MEM has the potential to reposition in the treatment of inflammatory diseases with the advantages of established safety and clinical data.
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Affiliation(s)
- Guillermo García-Laínez
- Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
| | - Mónica Sancho
- Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera, 3, 46012, Valencia, Spain.
| | - Vanessa García-Bayarri
- Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera, 3, 46012, Valencia, Spain
| | - Mar Orzáez
- Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera, 3, 46012, Valencia, Spain.
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Harding A, Robinson S, Crean S, Singhrao SK. Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer's Disease? J Alzheimers Dis 2018; 58:337-348. [PMID: 28453484 DOI: 10.3233/jad-170046] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A risk factor relationship exists between periodontal disease and Alzheimer's disease (AD) via tooth loss, and improved memory following dental intervention. This links the microbial contribution from indigenous oral periodontal pathogens to the manifestation of chronic conditions, such as AD. Here, we use Porphyromonas gingivalis infection to illustrate its effect on mental health. P. gingivalis infection, in its primary sub-gingival niche, can cause polymicrobial synergy and dysbiosis. Dysbiosis describes the residency of select commensals from the oral cavity following co-aggregation around the dominant keystone pathogen, such as P. gingivalis, to gain greater virulence. The initial process involves P. gingivalis disturbing neutrophil mediated innate immune responses in the healthy gingivae and then downregulating adaptive immune cell differentiation and development to invade, and subsequently, establish new dysbiotic bacterial communities. Immune responses affect the host in general and functionally via dietary adjustments caused by tooth loss. Studies from animals orally infected with P. gingivalis confirm this bacterium can transmigrate to distant organ sites (the brain) and contribute toward peripheral and intracerebral inflammation, and compromise vascular and microvascular integrity. In another study, P. gingivalis infection caused sleep pattern disturbances by altering glial cell light/dark molecular clock activity, and this, in turn, can affect the clearance of danger associated molecular patterns, such as amyloid-β, via the glymphatic system. Since P. gingivalis can transmigrate to the brain and modulate organ-specific inflammatory innate and adaptive immune responses, this paper explores whether better management of indigenous periodontal bacteria could delay/prevent the onset and/or progression of dementia.
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Gao J, Cui JZ, To E, Cao S, Matsubara JA. Evidence for the activation of pyroptotic and apoptotic pathways in RPE cells associated with NLRP3 inflammasome in the rodent eye. J Neuroinflammation 2018; 15:15. [PMID: 29329580 PMCID: PMC5766992 DOI: 10.1186/s12974-018-1062-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 01/09/2018] [Indexed: 12/24/2022] Open
Abstract
Background Age-related macular degeneration (AMD) is a devastating eye disease causing irreversible vision loss in the elderly. Retinal pigment epithelium (RPE), the primary cell type that is afflicted in AMD, undergoes programmed cell death in the late stages of the disease. However, the exact mechanisms for RPE degeneration in AMD are still unresolved. The prevailing theories consider that each cell death pathway works independently and without regulation of each other. Building upon our previous work in which we induced a short burst of inflammasome activity in vivo, we now investigate the effects of prolonged inflammasome activity on RPE cell death mechanisms in rats. Methods Long-Evans rats received three intravitreal injections of amyloid beta (Aβ), once every 4 days, and were sacrificed at day 14. The vitreous samples were collected to assess the levels of secreted cytokines. The inflammasome activity was evaluated by both immunohistochemistry and western blot. The types of RPE cell death mechanisms were determined using specific cell death markers and morphological characterizations. Results We found robust inflammasome activation evident by enhanced caspase-1 immunoreactivity, augmented NF-κB nuclear translocalization, increased IL-1β vitreal secretion, and IL-18 protein levels. Moreover, we observed elevated proteolytic cleavage of caspase-3 and gasdermin D, markers for apoptosis and pyroptosis, respectively, in RPE-choroid tissues. There was also a significant reduction in the anti-apoptotic factor, X-linked inhibitor of apoptosis protein, consistent with the overall changes of RPE cells. Morphological analysis showed phenotypic characteristics of pyroptosis including RPE cell swelling. Conclusions Our data suggest that two cell death pathways, pyroptosis and apoptosis, were activated in RPE cells after exposure to prolonged inflammasome activation, induced by a drusen component, Aβ. The involvement of two distinct cell death pathways in RPE sheds light on the potential interplay between these pathways and provides insights on the future development of therapeutic strategies for AMD. Electronic supplementary material The online version of this article (10.1186/s12974-018-1062-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jiangyuan Gao
- Department of Ophthalmology and Visual Sciences, Eye Care Centre, Faculty of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, BC, V5Z 3N9, Canada
| | - Jing Z Cui
- Department of Ophthalmology and Visual Sciences, Eye Care Centre, Faculty of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, BC, V5Z 3N9, Canada
| | - Eleanor To
- Department of Ophthalmology and Visual Sciences, Eye Care Centre, Faculty of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, BC, V5Z 3N9, Canada
| | - Sijia Cao
- Department of Ophthalmology and Visual Sciences, Eye Care Centre, Faculty of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, BC, V5Z 3N9, Canada
| | - Joanne A Matsubara
- Department of Ophthalmology and Visual Sciences, Eye Care Centre, Faculty of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, BC, V5Z 3N9, Canada.
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45
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Zhao Y, Cong L, Jaber V, Lukiw WJ. Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer's Disease Brain. Front Immunol 2017; 8:1064. [PMID: 28928740 PMCID: PMC5591429 DOI: 10.3389/fimmu.2017.01064] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/16/2017] [Indexed: 12/16/2022] Open
Abstract
Abundant clinical, epidemiological, imaging, genetic, molecular, and pathophysiological data together indicate that there occur an unusual inflammatory reaction and a disruption of the innate-immune signaling system in Alzheimer’s disease (AD) brain. Despite many years of intense study, the origin and molecular mechanics of these AD-relevant pathogenic signals are still not well understood. Here, we provide evidence that an intensely pro-inflammatory bacterial lipopolysaccharide (LPS), part of a complex mixture of pro-inflammatory neurotoxins arising from abundant Gram-negative bacilli of the human gastrointestinal (GI) tract, are abundant in AD-affected brain neocortex and hippocampus. For the first time, we provide evidence that LPS immunohistochemical signals appear to aggregate in clumps in the parenchyma in control brains, and in AD, about 75% of anti-LPS signals were clustered around the periphery of DAPI-stained nuclei. As LPS is an abundant secretory product of Gram-negative bacilli resident in the human GI-tract, these observations suggest (i) that a major source of pro-inflammatory signals in AD brain may originate from internally derived noxious exudates of the GI-tract microbiome; (ii) that due to aging, vascular deficits or degenerative disease these neurotoxic molecules may “leak” into the systemic circulation, cerebral vasculature, and on into the brain; and (iii) that this internal source of microbiome-derived neurotoxins may play a particularly strong role in shaping the human immune system and contributing to neural degeneration, particularly in the aging CNS. This “Perspectives” paper will further highlight some very recent developments that implicate GI-tract microbiome-derived LPS as an important contributor to inflammatory-neurodegeneration in the AD brain.
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Affiliation(s)
- Yuhai Zhao
- Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States.,Department of Anatomy and Cell Biology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Lin Cong
- Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States.,Department of Neurology, Shengjing Hospital, China Medical University, Heping District, Shenyang, China
| | - Vivian Jaber
- Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Walter J Lukiw
- Neuroscience Center, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States.,Department of Neurology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States.,Department of Ophthalmology, Louisiana State University School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United States
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46
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Cheng Y, Wei Y, Yang W, Song Y, Shang H, Cai Y, Wu Z, Zhao W. Cordycepin confers neuroprotection in mice models of intracerebral hemorrhage via suppressing NLRP3 inflammasome activation. Metab Brain Dis 2017; 32:1133-1145. [PMID: 28401330 DOI: 10.1007/s11011-017-0003-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/27/2017] [Indexed: 12/31/2022]
Abstract
Neuroinflammation has been recognized as a major contributor to brain injury caused by intracerebral hemorrhage (ICH). Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome acts as an important mediator of inflammatory response in various inflammation-related diseases including hemorrhagic insults. Cordycepin has recently been shown to possess anti-inflammatory effect; however, its role and the possible underlying mechanisms in ICH remain unclear. This study was designed to investigate the neuroprotective effect of cordycepin in mice models of ICH and to elucidate the underlying molecular mechanisms. ICH was induced in male ICR mice by injecting autologous blood infusion stereotactically. Cordycepin was then given intraperitoneally (i.p.) at 30 min after ICH induction. The results demonstrated that NLRP3 inflammasome was activated and exacerbated the inflammatory progression after ICH. Cordycepin treatment significantly alleviated neurological deficits, brain edema, and perihematomal tissue damage following ICH. These changes were accompanied by downregulated NLRP3 inflammasome components expression and a reduction of production and release of inflammasome substrates interleukin-1beta (IL-1β) and interleukin-18 (IL-18). Furthermore, cordycepin ameliorated neuronal death in the perihematomal regions, accompanied by a large reduction in the expression of high-mobility group protein B 1 (HMGB1) post-ICH. In conclusion, this study provides in vivo evidence that cordycepin confers neuroprotective effect in the models of ICH, possibly through the suppression of NLRP3 inflammasome activation.
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Affiliation(s)
- Yijun Cheng
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Yongxu Wei
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Wenlei Yang
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Yaying Song
- Department of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Hanbing Shang
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Yu Cai
- Department of Neurosurgery, North Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201800, People's Republic of China.
| | - Zhebao Wu
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
| | - Weiguo Zhao
- Department of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
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Zhang Z, Ma X, Xia Z, Chen J, Liu Y, Chen Y, Zhu J, Li J, Yu H, Zong Y, Lu G. NLRP3 inflammasome activation mediates fatigue-like behaviors in mice via neuroinflammation. Neuroscience 2017; 358:115-123. [PMID: 28684277 DOI: 10.1016/j.neuroscience.2017.06.048] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 06/23/2017] [Accepted: 06/23/2017] [Indexed: 12/20/2022]
Abstract
Numerous experimental and clinical studies have suggested that the interaction between the immune system and the brain plays an important role in the pathophysiology of chronic fatigue syndrome (CFS). The NLRP3 inflammasome is an important part of the innate immune system. This complex regulates proinflammatory cytokine interleukin-1β (IL-1β) maturation, which triggers different kinds of immune-inflammatory reactions. We employed repeated forced swims to establish a model of CFS in mice. NLRP3 knockout (KO) mice were also used to explore NLRP3 inflammasome activation in the mechanisms of CFS, using the same treatment. After completing repeated swim tests, the mice displayed fatigue-like behaviors, including locomotor activity and reduced fall-off time on the rota-rod test, which was accompanied by significantly higher mature IL-1β level in the prefrontal cortex (PFC) and malondialdehyde (MDA) level in serum. We also found increased NLRP3 protein expression, NLRP3 inflammasome formation and increased mature IL-1β production in the PFC, relative to untreated mice. The NLRP3 KO mice displayed significantly moderated fatigue behaviors along with decreased PFC and serum IL-1β levels under the same treatment. These findings demonstrated the involvement of NLRP3 inflammasome activation in the mechanism of swimming-induced fatigue. Future therapies targeting the NLRP3/IL-1β pathway may have significant potential for fatigue prevention and treatment.
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Affiliation(s)
- Ziteng Zhang
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Xiujuan Ma
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Zhenna Xia
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Jikuai Chen
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Yangang Liu
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Yongchun Chen
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Jiangbo Zhu
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Jinfeng Li
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Huaiyu Yu
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China
| | - Ying Zong
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China.
| | - Guocai Lu
- Department of Health Toxicology, College of Tropical Medicine and Public Health, Second Military Medical University, Shanghai 200433, China; Suzhou CTI Biotechnology Co., Ltd., Jiangsu 215300, China.
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Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, Davies M, West NX, Allen SJ. 16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer's Post-Mortem Brain. Front Aging Neurosci 2017; 9:195. [PMID: 28676754 PMCID: PMC5476743 DOI: 10.3389/fnagi.2017.00195] [Citation(s) in RCA: 230] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 05/31/2017] [Indexed: 12/13/2022] Open
Abstract
The neurological deterioration associated with Alzheimer's disease (AD), involving accumulation of amyloid-beta peptides and neurofibrillary tangles, is associated with evident neuroinflammation. This is now seen to be a significant contributor to pathology. Recently the tenet of the privileged status of the brain, regarding microbial compromise, has been questioned, particularly in terms of neurodegenerative diseases. It is now being considered that microbiological incursion into the central nervous system could be either an initiator or significant contributor to these. This is a novel study using 16S ribosomal gene-specific Next generation sequencing (NGS) of extracted brain tissue. A comparison was made of the bacterial species content of both frozen and formaldehyde fixed sections of a small cohort of Alzheimer-affected cases with those of cognitively unimpaired (normal). Our findings suggest an increase in bacterial populations in Alzheimer brain tissue compared with normal.
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Affiliation(s)
- David C. Emery
- School of Clinical Sciences, Faculty of Health Sciences, University of BristolBristol, United Kingdom
| | | | - Tom E. Batstone
- School of Biological Sciences, Life Sciences, University of BristolBristol, United Kingdom
| | - Christy M. Waterfall
- School of Biological Sciences, Life Sciences, University of BristolBristol, United Kingdom
| | - Jane A. Coghill
- School of Biological Sciences, Life Sciences, University of BristolBristol, United Kingdom
| | | | - Maria Davies
- School of Oral and Dental SciencesBristol, United Kingdom
| | - Nicola X. West
- School of Oral and Dental SciencesBristol, United Kingdom
| | - Shelley J. Allen
- School of Clinical Sciences, Faculty of Health Sciences, University of BristolBristol, United Kingdom
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Holmstrup P, Damgaard C, Olsen I, Klinge B, Flyvbjerg A, Nielsen CH, Hansen PR. Comorbidity of periodontal disease: two sides of the same coin? An introduction for the clinician. J Oral Microbiol 2017; 9:1332710. [PMID: 28748036 PMCID: PMC5508374 DOI: 10.1080/20002297.2017.1332710] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Accepted: 01/07/2017] [Indexed: 12/14/2022] Open
Abstract
Increasing evidence has suggested an independent association between periodontitis and a range of comorbidities, for example cardiovascular disease, type 2 diabetes, rheumatoid arthritis, osteoporosis, Parkinson’s disease, Alzheimer’s disease, psoriasis, and respiratory infections. Shared inflammatory pathways are likely to contribute to this association, but distinct causal mechanisms remain to be defined. Some of these comorbid conditions may improve by periodontal treatment, and a bidirectional relationship may exist, where, for example, treatment of diabetes can improve periodontal status. The present article presents an overview of the evidence linking periodontitis with selected systemic diseases and calls for increased cooperation between dentists and medical doctors to provide optimal screening, treatment, and prevention of both periodontitis and its comorbidities.
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Affiliation(s)
- Palle Holmstrup
- Section for Periodontology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Christian Damgaard
- Section for Periodontology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Ingar Olsen
- Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Björn Klinge
- Department of Periodontology, Faculty of Odontology, Malmö University, Malmö, Sweden.,Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Claus Henrik Nielsen
- Section for Periodontology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Peter Riis Hansen
- Section for Periodontology, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Cardiology Department, Herlev and Gentofte Hospital, Hellerup, Denmark
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50
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Thangavel R, Kempuraj D, Zaheer S, Raikwar S, Ahmed ME, Selvakumar GP, Iyer SS, Zaheer A. Glia Maturation Factor and Mitochondrial Uncoupling Proteins 2 and 4 Expression in the Temporal Cortex of Alzheimer's Disease Brain. Front Aging Neurosci 2017; 9:150. [PMID: 28572767 PMCID: PMC5435744 DOI: 10.3389/fnagi.2017.00150] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Accepted: 05/03/2017] [Indexed: 11/13/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by the presence of neuropathological lesions containing amyloid plaques (APs) and neurofibrillary tangles (NFTs). AD is associated with mitochondrial dysfunctions, neuroinflammation and neurodegeneration in the brain. We have previously demonstrated enhanced expression of the proinflammatory protein glia maturation factor (GMF) in glial cells near APs and NFTs in the AD brains. Parahippocampal gyrus consisting of entorhinal and perirhinal subdivisions of temporal cortex is the first brain region affected during AD pathogenesis. Current paradigm implicates oxidative stress-mediated neuronal damage contributing to the early pathology in AD with mitochondrial membrane potential regulating reactive oxygen species (ROS) production. The inner mitochondrial membrane anion transporters called the uncoupling proteins (UCPs), function as regulators of cellular homeostasis by mitigating oxidative stress. In the present study, we have analyzed the expression of GMF and mitochondrial UCP2 and UCP4 in the parahippocampal gyrus of AD and non-AD brains by immunostaining techniques. APs were detected by thioflavin-S fluorescence staining or immunohistochemistry (IHC) with 6E10 antibody. Our current results suggest that upregulation of GMF expression is associated with down-regulation of UCP2 as well as UCP4 in the parahippocampal gyrus of AD brains as compared to non-AD brains. Further, GMF expression is associated with up-regulation of inducible nitric oxide synthase (iNOS), the enzyme that induces the production of nitric oxide (NO), as well as nuclear factor kB p65 (NF-κB p65) expression. Also, GMF appeared to localize to the mitochondria in AD brains. Based on our current observations, we propose that enhanced expression of GMF down-regulates mitochondrial UCP2 and UCP4 thereby exacerbating AD pathophysiology and this effect is potentially mediated by iNOS and NF-κB. Thus, GMF functions as an activator protein that interferes with the cytoprotective mechanisms in AD brains.
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Affiliation(s)
- Ramasamy Thangavel
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of MissouriColumbia, MO, United States
- Research Services, Harry S. Truman Memorial Veterans HospitalColumbia, MO, United States
| | - Duraisamy Kempuraj
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of MissouriColumbia, MO, United States
- Research Services, Harry S. Truman Memorial Veterans HospitalColumbia, MO, United States
| | - Smita Zaheer
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of MissouriColumbia, MO, United States
| | - Sudhanshu Raikwar
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of MissouriColumbia, MO, United States
| | - Mohammad E. Ahmed
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of MissouriColumbia, MO, United States
| | | | - Shankar S. Iyer
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of MissouriColumbia, MO, United States
| | - Asgar Zaheer
- Department of Neurology, Center for Translational Neuroscience, School of Medicine, University of MissouriColumbia, MO, United States
- Research Services, Harry S. Truman Memorial Veterans HospitalColumbia, MO, United States
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