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Ramesh M, Govindaraju T. MiR-7a-Klf4 axis as a regulator and therapeutic target of neuroinflammation and ferroptosis in Alzheimer's disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.24.644978. [PMID: 40196619 PMCID: PMC11974717 DOI: 10.1101/2025.03.24.644978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Neuroinflammation and ferroptosis significantly contribute to neuronal death in Alzheimer's disease (AD) and other neurodegenerative disorders. MicroRNAs (miRNAs) are crucial regulators of these pathological processes. We employed transcriptomic analysis in an APP/PSEN1 Tg AD mouse model to identify dysregulated miRNAs and construct a miRNA-mRNA-pathway network. We discovered increased miR7a expression in the AD brain, targeting Krüppel-like factor 4 (Klf4), a transcriptional factor implicated in Aβ oligomer-induced neuroinflammation and RSL3-induced neuronal ferroptosis. Elevated Klf4 levels in AD mice brains suggest its involvement in AD pathology. The miR-7a mediated silencing of Klf4 alleviates neuroinflammation by modulating NF-κB, iNOS, and NLRP3 pathways, and inhibition of ferroptosis by targeting labile iron levels, GPX4, Nrf2 pathway, and mitochondrial damage. These findings highlight the neuroprotective role of miR-7a and its potential as RNA therapeutic. Pharmacological targeting of the miR-7a-Klf4 axis with blood-brain-barrier (BBB)-permeable compound effectively mitigates neuroinflammation and ferroptosis, suggesting the miR-7a-Klf4 axis as a novel therapeutic target for AD. GRAPHICAL ABSTRACT
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Gong Y, Haeri M, Zhang X, Li Y, Liu A, Wu D, Zhang Q, Jazwinski SM, Zhou X, Wang X, Zhang K, Jiang L, Chen YP, Yan X, Swerdlow RH, Shen H, Deng HW. Stereo-seq of the prefrontal cortex in aging and Alzheimer's disease. Nat Commun 2025; 16:482. [PMID: 39779708 PMCID: PMC11711495 DOI: 10.1038/s41467-024-54715-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/20/2024] [Indexed: 01/11/2025] Open
Abstract
Aging increases the risk for Alzheimer's disease (AD), driving pathological changes like amyloid-β (Aβ) buildup, inflammation, and oxidative stress, especially in the prefrontal cortex (PFC). We present the first subcellular-resolution spatial transcriptome atlas of the human prefrontal cortex (PFC), generated with Stereo-seq from six male AD cases at varying neuropathological stages and six age-matched male controls. Our analyses revealed distinct transcriptional alterations across PFC layers, highlighted disruptions in laminar structure, and exposed AD-related shifts in layer-to-layer and cell-cell interactions. Notably, we identified genes highly upregulated in stressed neurons and nearby glial cells, where AD diminished stress-response interactions that promote Aβ clearance. Further, cell-type-specific co-expression analysis highlighted three neuronal modules linked to neuroprotection, protein dephosphorylation, and Aβ regulation, with all modules downregulated as AD progresses. We identified ZNF460 as a transcription factor regulating these modules, offering a potential therapeutic target. In summary, this spatial transcriptome atlas provides valuable insight into AD's molecular mechanisms.
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Affiliation(s)
- Yun Gong
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Mohammad Haeri
- Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, MO, 66160, USA
| | - Xiao Zhang
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Yisu Li
- Department of Cell and Molecular Biology, School of Science of Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Anqi Liu
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Di Wu
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Qilei Zhang
- School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410008, China
| | - S Michal Jazwinski
- Tulane Center for Aging, Deming Department of Medicine, Tulane University School of Medicne, New Orleans, LA, 70112, USA
| | - Xiang Zhou
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Xiaoying Wang
- Clinical Neuroscience Research Center, Departments of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Kai Zhang
- Department of Environmental Health Sciences, College of Integrated Health Sciences, University at Albany, Albany, NY, 12222, USA
| | - Lindong Jiang
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Yi-Ping Chen
- Department of Cell and Molecular Biology, School of Science of Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Xiaoxin Yan
- School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Russell H Swerdlow
- Department of Neurology, University of Kansas Medical Center, Kansas City, MO, 66160, USA.
| | - Hui Shen
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
| | - Hong-Wen Deng
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
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Kiouri DP, Chasapis CT, Mavromoustakos T, Spiliopoulou CA, Stefanidou ME. Zinc and its binding proteins: essential roles and therapeutic potential. Arch Toxicol 2025; 99:23-41. [PMID: 39508885 DOI: 10.1007/s00204-024-03891-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 10/09/2024] [Indexed: 11/15/2024]
Abstract
Zinc is an essential micronutrient that participates in a multitude of cellular and biochemical processes. It is indispensable for normal growth and the maintenance of physiological functions. As one of the most significant trace elements in the body, zinc fulfills three primary biological roles: catalytic, structural, and regulatory. It serves as a cofactor in over 300 enzymes, and more than 3000 proteins require zinc, underscoring its crucial role in numerous physiological processes such as cell division and growth, immune function, tissue maintenance, as well as synthesis protein and collagen synthesis. Zinc deficiency has been linked to increased oxidative stress and inflammation, which may contribute to the pathogenesis of a multitude of diseases, like neurological disorders and cancer. In addition, zinc is a key constituent of zinc-binding proteins, which play a pivotal role in maintaining cellular zinc homeostasis. This review aims to update and expand upon the understanding of zinc biology, highlighting the fundamental roles of zinc in biological processes and the health implications of zinc deficiency. This work also explores the diverse functions of zinc in immune regulation, cellular growth, and neurological health, emphasizing the need for further research to fully elucidate the therapeutic potential of zinc supplementation in disease prevention and management.
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Affiliation(s)
- Despoina P Kiouri
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635, Athens, Greece
- Department of Chemistry, Laboratory of Organic Chemistry, National and Kapodistrian University of Athens, 15772, Athens, Greece
| | - Christos T Chasapis
- Institute of Chemical Biology, National Hellenic Research Foundation, 11635, Athens, Greece.
| | - Thomas Mavromoustakos
- Department of Chemistry, Laboratory of Organic Chemistry, National and Kapodistrian University of Athens, 15772, Athens, Greece
| | - Chara A Spiliopoulou
- Department of Forensic Medicine and Toxicology, School of Medicine, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Maria E Stefanidou
- Department of Forensic Medicine and Toxicology, School of Medicine, National and Kapodistrian University of Athens, 11527, Athens, Greece.
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Song L, Liu H, Yang W, Yin H, Wang J, Guo M, Yang Z. Biological functions of the m6A reader YTHDF2 and its role in central nervous system disorders. Biochem Pharmacol 2024; 230:116576. [PMID: 39424201 DOI: 10.1016/j.bcp.2024.116576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/11/2024] [Accepted: 10/14/2024] [Indexed: 10/21/2024]
Abstract
N6-methyladenosine (m6A) is a prevalent mRNA modification in eukaryotic cells, characterized by its reversible nature. YTH structural domain family protein 2 (YTHDF2), a key reader of m6A, plays a crucial role in identifying and binding m6A-containing RNAs, thereby influencing RNA metabolism through various functional mechanisms. The upstream and downstream targets of YTHDF2 are critical in the pathogenesis of various central nervous system (CNS) diseases, affecting disease development by regulating signaling pathways and gene expression. This paper provides an overview of current research on the role of YTHDF2 in CNS diseases and investigates the regulatory mechanisms by which YTHDF2 influences the development of these conditions. This exploration aims to improve understanding of disease pathogenesis and offer novel insights for the targeted prevention and treatment of neurological disorders.
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Affiliation(s)
- Lili Song
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, China
| | - Huimin Liu
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, China
| | - Weiyu Yang
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, China
| | - Hongqing Yin
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, China
| | - Jiayi Wang
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, China
| | - Maojuan Guo
- Department of Pathology, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, China
| | - Zhen Yang
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, China.
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Xue C, Liu B, Zhao Y, Wang X, Sun ZW, Xie F, Qian LJ. Chronic stress disturbed the metabolism of homocysteine in mouse hippocampus and prefrontal cortex. Neuroscience 2024; 563:63-73. [PMID: 39521319 DOI: 10.1016/j.neuroscience.2024.11.006] [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: 06/27/2024] [Revised: 10/21/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Stress is an independent risk factor for cognitive impairment, with elevated plasma homocysteine (HCY) levels playing a crucial role in stress-induced cognitive decline. While the rise in plasma HCY levels is linked to abnormal peripheral catabolism, the impact of stress on HCY catabolism in the brain remains unclear. This study investigated the effect of stress on HCY metabolism in the brain by analyzing HCY and its metabolic enzymes in the hippocampus and prefrontal cortex. The results showed a significant decrease in enzymes MS (methionine-synthase), CBS (cystathionineβ-synthase), and CSE (cystathionine γ-lyase) in these brain regions of mice subjected to 3 weeks of restraint stress, leading to HCY accumulation. Additionally, the enzyme MTHFR (methylenetetrahydrofolate reductase) remained unchanged. Immunofluorescence double-labeling revealed the downregulation of HCY metabolic enzymes in neurons of stressed mice. The transcription factor KLF4 (Kruppel-likefactor4), known for its inhibitory role, increased after stress or glucocorticoid treatment and suppressed the expression of MS, CBS, and CSE, contributing to elevated HCY levels in the brain. These findings offer new insights into the impairment of HCY catabolism in the stressed brain, suggesting that the downregulation of HCY metabolic enzymes may underlie HCY accumulation and exacerbate stress-induced cognitive dysfunction.
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Affiliation(s)
- Cong Xue
- Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100039, China
| | - Bing Liu
- Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100039, China
| | - Yun Zhao
- Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100039, China
| | - Xue Wang
- Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100039, China
| | - Zhao-Wei Sun
- Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100039, China
| | - Fang Xie
- Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100039, China.
| | - Ling-Jia Qian
- Beijing Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100039, China.
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Liang Y, Zhao J, Dai T, Li X, Chen L, He Z, Guo M, Zhao J, Xu L. A review of KLF4 and inflammatory disease: Current status and future perspective. Pharmacol Res 2024; 207:107345. [PMID: 39134187 DOI: 10.1016/j.phrs.2024.107345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 08/03/2024] [Accepted: 08/07/2024] [Indexed: 08/15/2024]
Abstract
Inflammation is the response of the human body to injury, infection, or other abnormal states, which is involved in the development of many diseases. As a member of the Krüppel-like transcription factors (KLFs) family, KLF4 plays a crucial regulatory role in physiological and pathological processes due to its unique dual domain of transcriptional activation and inhibition. A growing body of evidence has demonstrated that KLF4 plays a pivotal role in the pathogenesis of various inflammatory disorders, including inflammatory bowel disease, osteoarthritis, renal inflammation, pneumonia, neuroinflammation, and so on. Consequently, KLF4 has emerged as a promising new therapeutic target for inflammatory diseases. This review systematically generalizes the molecular regulatory network, specific functions, and mechanisms of KLF4 to elucidate its complex roles in inflammatory diseases. An in-depth study on the biological function of KLF4 is anticipated to offer a novel research perspective and potential intervention strategies for inflammatory diseases.
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Affiliation(s)
- Yidan Liang
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Jiamin Zhao
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Tengkun Dai
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Xin Li
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Longqin Chen
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Zhixu He
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou 563000, China
| | - Mengmeng Guo
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Juanjuan Zhao
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China.
| | - Lin Xu
- Special Key Laboratory of Gene Detection &Therapy of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, China; Department of Immunology, Zunyi Medical University, Zunyi, Guizhou 563000, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou 563000, China.
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Li B, Piao J, Piao X, Geng Z, Cheng Z, Zou X, Jiang H. Effect of Kruppel-like factor 4 on PTZ-induced acute seizure mice. J Cell Mol Med 2024; 28:e18578. [PMID: 39234952 PMCID: PMC11375452 DOI: 10.1111/jcmm.18578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 06/13/2024] [Accepted: 07/16/2024] [Indexed: 09/06/2024] Open
Abstract
Kruppel-like factor 4 (Klf4) is a transcription factor that is involved in neuronal regeneration and the development of glutamatergic systems. However, it is unknown whether Klf4 is involved in acute seizure. To investigate the potential role of Klf4 in pentylenetetrazol (PTZ)-induced seizure, western blotting, immunofluorescence, behaviour test and electrophysiology were conducted in this study. We found that Klf4 protein and mRNA expression were increased in both the hippocampus (HP) and prefrontal cortex (PFC) after PTZ-induced seizure in mice. HP-specific knockout (KO) of Klf4 in mice decreased protein expression of Klf4 and the down-stream Klf4 target tumour protein 53 (TP53/P53). These molecular changes are accompanied by increased seizure latency, reduced immobility time in the forced swimming test and tail suspension test. Reduced hippocampal protein levels for synaptic proteins, including glutamate receptor 1 (GRIA1/GLUA1) and postsynaptic density protein 95 (DLG4/PSD95), were also observed after Klf4-KO, while increased mRNA levels of complement proteins were observed for complement component 1q subcomponent A (C1qa), complement component 1q subcomponent B (C1qb), complement component 1q subcomponent C (C1qc), complement component 3 (C3), complement component 4A (C4a) and complement component 4B (C4b). Moreover, c-Fos expression induced by PTZ was reduced by hippocampal conditional KO of Klf4. Electrophysiology showed that PTZ-induced action potential frequency was decreased by overexpression of Klf4. In conclusion, these findings suggest that Klf4 plays an important role in regulating PTZ-induced seizures and therefore constitutes a new molecular target that should be explored for the development of antiepileptic drugs.
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Affiliation(s)
- Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, Second Hospital of Jilin University, Changchun, People's Republic of China
- Department of Medical Research Centar, Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Jingjing Piao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, Second Hospital of Jilin University, Changchun, People's Republic of China
- Department of Medical Research Centar, Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Xinmiao Piao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, Second Hospital of Jilin University, Changchun, People's Republic of China
- Department of Medical Research Centar, Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Zihui Geng
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, Second Hospital of Jilin University, Changchun, People's Republic of China
- Department of Medical Research Centar, Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Ziqian Cheng
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, Second Hospital of Jilin University, Changchun, People's Republic of China
- Department of Medical Research Centar, Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Xiaohan Zou
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, Second Hospital of Jilin University, Changchun, People's Republic of China
- Department of Medical Research Centar, Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Huiyi Jiang
- Department of Pediatrics, The First Hospital of Jilin University, Changchun, People's Republic of China
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Zamanian MY, Golmohammadi M, Amin RS, Bustani GS, Romero-Parra RM, Zabibah RS, Oz T, Jalil AT, Soltani A, Kujawska M. Therapeutic Targeting of Krüppel-Like Factor 4 and Its Pharmacological Potential in Parkinson's Disease: a Comprehensive Review. Mol Neurobiol 2024; 61:3596-3606. [PMID: 37996730 PMCID: PMC11087351 DOI: 10.1007/s12035-023-03800-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 11/10/2023] [Indexed: 11/25/2023]
Abstract
Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, is found in different human tissues and shows diverse regulatory activities in a cell-dependent manner. In the brain, KLF4 controls various neurophysiological and neuropathological processes, and its contribution to various neurological diseases has been widely reported. Parkinson's disease (PD) is an age-related neurodegenerative disease that might have a connection with KLF4. In this review, we discussed the potential implication of KLF4 in fundamental molecular mechanisms of PD, including aberrant proteostasis, neuroinflammation, apoptosis, oxidative stress, and iron overload. The evidence collected herein sheds new light on KLF4-mediated pathways, which manipulation appears to be a promising therapeutic target for PD management. However, there is a gap in the knowledge on this topic, and extended research is required to understand the translational value of the KLF4-oriented therapeutical approach in PD.
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Affiliation(s)
- Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, 6718773654, Iran
| | - Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran
| | | | | | | | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Tuba Oz
- Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806, Poznan, Poland
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Afsaneh Soltani
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1988873554, Iran.
| | - Małgorzata Kujawska
- Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3, 60-806, Poznan, Poland.
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Gong Y, Haeri M, Zhang X, Li Y, Liu A, Wu D, Zhang Q, Jazwinski SM, Zhou X, Wang X, Jiang L, Chen YP, Yan X, Swerdlow RH, Shen H, Deng HW. Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer's Disease in Human Prefrontal Cortex at Single-Nucleus Resolution. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.21.24306783. [PMID: 38826275 PMCID: PMC11142279 DOI: 10.1101/2024.05.21.24306783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Aging significantly elevates the risk for Alzheimer's disease (AD), contributing to the accumulation of AD pathologies, such as amyloid-β (Aβ), inflammation, and oxidative stress. The human prefrontal cortex (PFC) is highly vulnerable to the impacts of both aging and AD. Unveiling and understanding the molecular alterations in PFC associated with normal aging (NA) and AD is essential for elucidating the mechanisms of AD progression and developing novel therapeutics for this devastating disease. In this study, for the first time, we employed a cutting-edge spatial transcriptome platform, STOmics® SpaTial Enhanced Resolution Omics-sequencing (Stereo-seq), to generate the first comprehensive, subcellular resolution spatial transcriptome atlas of the human PFC from six AD cases at various neuropathological stages and six age, sex, and ethnicity matched controls. Our analyses revealed distinct transcriptional alterations across six neocortex layers, highlighted the AD-associated disruptions in laminar architecture, and identified changes in layer-to-layer interactions as AD progresses. Further, throughout the progression from NA to various stages of AD, we discovered specific genes that were significantly upregulated in neurons experiencing high stress and in nearby non-neuronal cells, compared to cells distant from the source of stress. Notably, the cell-cell interactions between the neurons under the high stress and adjacent glial cells that promote Aβ clearance and neuroprotection were diminished in AD in response to stressors compared to NA. Through cell-type specific gene co-expression analysis, we identified three modules in excitatory and inhibitory neurons associated with neuronal protection, protein dephosphorylation, and negative regulation of Aβ plaque formation. These modules negatively correlated with AD progression, indicating a reduced capacity for toxic substance clearance in AD subject samples. Moreover, we have discovered a novel transcription factor, ZNF460, that regulates all three modules, establishing it as a potential new therapeutic target for AD. Overall, utilizing the latest spatial transcriptome platform, our study developed the first transcriptome-wide atlas with subcellular resolution for assessing the molecular alterations in the human PFC due to AD. This atlas sheds light on the potential mechanisms underlying the progression from NA to AD.
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Affiliation(s)
- Yun Gong
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Mohammad Haeri
- Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, MO, 66160, USA
| | - Xiao Zhang
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Yisu Li
- Department of Cell and Molecular Biology, School of Science of Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Anqi Liu
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Di Wu
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Qilei Zhang
- School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410008, China
| | - S. Michal Jazwinski
- Tulane Center for Aging, Deming Department of Medicine, Tulane University School of Medicne, New Orleans, LA 70112, USA
| | - Xiang Zhou
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Xiaoying Wang
- Clinical Neuroscience Research Center, Departments of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Lindong Jiang
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Yi-Ping Chen
- Department of Cell and Molecular Biology, School of Science of Engineering, Tulane University, New Orleans, LA, 70118, USA
| | - Xiaoxin Yan
- School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410008, China
| | - Russell H. Swerdlow
- Department of Neurology, University of Kansas Medical Center, Kansas City, MO, 66160, USA
| | - Hui Shen
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Hong-Wen Deng
- Tulane Center for Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University, New Orleans, LA, 70112, USA
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10
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Sun L, Wang Q, Ai J. The underlying roles and neurobiological mechanisms of music-based intervention in Alzheimer's disease: A comprehensive review. Ageing Res Rev 2024; 96:102265. [PMID: 38479478 DOI: 10.1016/j.arr.2024.102265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 02/25/2024] [Accepted: 03/04/2024] [Indexed: 03/19/2024]
Abstract
Non-pharmacological therapy has gained popularity in the intervention of Alzheimer's disease (AD) due to its apparent therapeutic effectiveness and the limitation of biological drug. A wealth of research indicates that music interventions can enhance cognition, mood and behavior in individuals with AD. Nonetheless, the underlying mechanisms behind these improvements have yet to be fully and systematically delineated. This review aims to holistically review how music-based intervention (MBI) ameliorates abnormal emotion, cognition decline, and behavioral changes in AD patients. We cover several key dimensions: the regulation of MBIs on cerebral blood flow (CBF), their impact on neurotransmission (including GABAergic and monoaminergic transmissions), modulation of synaptic plasticity, and hormonal release. Additionally, we summarize the clinical applications and limitations of active music-based intervention (AMBI), passive music-based intervention (PMBI), and hybrid music-based intervention (HMBI). This thorough analysis enhances our understanding of the role of MBI in AD and supports the development of non-pharmacological therapeutic strategies.
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Affiliation(s)
- Liyang Sun
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, 157 Baojian Road, Harbin 150086, China
| | - Qin Wang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, 157 Baojian Road, Harbin 150086, China; Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin 150040, China; Heilongjiang Academy of Medical Sciences, 157 Baojian Road, Harbin 150086, China
| | - Jing Ai
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, 157 Baojian Road, Harbin 150086, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, 157 Baojian Road, Harbin 150086, China.
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11
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Liang X, Di F, Wei H, Liu N, Chen C, Wang X, Sun M, Zhang M, Li M, Zhang J, Zhang S. Functional identification of long non-coding RNAs induced by PM 2.5 in microglia through microarray analysis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 273:116136. [PMID: 38387142 DOI: 10.1016/j.ecoenv.2024.116136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/13/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
As a dominating air pollutant, atmospheric fine particulate matter within 2.5 μm in diameter (PM2.5) has attracted increasing attention from the researchers all over the world, which will lead to various adverse effects on the central nervous system (CNS), yet the potential mechanism is unclear. In this study, the microglia (BV2 cell line) were exposed to different concentrations of PM2.5 (5, 10 and 20 μg/cm2) for 24 h. It was found that PM2.5 could result in adverse effects on microglia such as decreased cell viability, structural damage and even cell death. And it was reported that long non-coding RNAs (lncRNAs) could participate in multitudinous neurological diseases. Therefore, the microarray analysis was conducted in order to disclose the underlying neurotoxicity mechanism of PM2.5 by ascertaining the differentially expressed lncRNAs (DElncRNAs). The consequences indicated that the DElncRNAs were enriched in various biological pathways, including ferroptosis, IL-17 signaling pathway and NOD-like receptor signaling pathway. Moreover, the cis- and trans-regulated mRNAs by DElncRNAs as well as the corresponding transcriptional factors (TFs) were observed, such as CEBPA, MYC, MEIS1 and KLF4. In summary, our study supplies some candidate libraries and potential preventive target against PM2.5-induced toxicity through targeting lncRNAs. Furthermore, the post-transcriptional regulation will contribute to the future research on PM2.5-induced neurotoxicity.
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Affiliation(s)
- Xue Liang
- School of Public Health, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China; Medical Science and Technology Innovation Center, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China.
| | - Fanglin Di
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
| | - Haiyun Wei
- School of Public Health, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
| | - Natong Liu
- School of Public Health, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
| | - Chao Chen
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
| | - Xinzhi Wang
- School of Public Health, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
| | - Meng Sun
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
| | - Min Zhang
- Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
| | - Meng Li
- Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
| | - Jie Zhang
- Medical Science and Technology Innovation Center, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
| | - Shuping Zhang
- Medical Science and Technology Innovation Center, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan, Shandong 250117, China
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12
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Zhang L, Zhu B, Zhou X, Ning H, Zhang F, Yan B, Chen J, Ma T. ZNF787 and HDAC1 Mediate Blood-Brain Barrier Permeability in an In Vitro Model of Alzheimer's Disease Microenvironment. Neurotox Res 2024; 42:12. [PMID: 38329647 DOI: 10.1007/s12640-024-00693-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 12/19/2023] [Accepted: 01/30/2024] [Indexed: 02/09/2024]
Abstract
The permeability of the blood-brain barrier (BBB) is increased in Alzheimer's disease (AD). This plays a key role in the instigation and maintenance of chronic inflammation during AD. Experiments using AD models showed that the increased permeability of the BBB was mainly caused by the decreased expression of tight junction-related proteins occludin and claudin-5. In this study, we found that ZNF787 and HDAC1 were upregulated in β-amyloid (Aβ)1-42-incubated endothelial cells, resulting in increased BBB permeability. Conversely, the silencing of ZNF787 and HDAC1 by RNAi led to reduced BBB permeability. The silencing of ZNF787 and HDAC1 enhanced the expression of occludin and claudin-5. Mechanistically, ZNF787 binds to promoter regions for occludin and claudin-5 and functions as a transcriptional regulator. Furthermore, we demonstrate that ZNF787 interacts with HDAC1, and this resulted in the downregulation of the expression of genes encoding tight junction-related proteins to increase in BBB permeability. Taken together, our study identifies critical roles for the interaction between ZNF787 and HDAC1 in regulating BBB permeability and the pathogenesis of AD.
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Affiliation(s)
- Lu Zhang
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
| | - Baicheng Zhu
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
| | - Xinxin Zhou
- Liaoning University of Traditional Chinese Medicine, Shenyang, 110034, China
| | - Hao Ning
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China
| | - Fengying Zhang
- Department of Neurology, Affiliated Nanhua Hospital, University of South China, Hengyang, 421001, China
| | - Bingju Yan
- Department of Cardiology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China
| | - Jiajia Chen
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Teng Ma
- Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, 110122, China.
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13
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Du B, Zhang J, Kong L, Shi H, Zhang D, Wang X, Yang C, Li P, Yao R, Liang C, Wu L, Huang Z. Ovarian Tumor Domain-Containing 7B Attenuates Pathological Cardiac Hypertrophy by Inhibiting Ubiquitination and Degradation of Krüppel-Like Factor 4. J Am Heart Assoc 2023; 12:e029745. [PMID: 38084712 PMCID: PMC10863784 DOI: 10.1161/jaha.123.029745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 08/15/2023] [Indexed: 12/20/2023]
Abstract
BACKGROUND Cardiac hypertrophy (CH) is a well-established risk factor for many cardiovascular diseases and a primary cause of mortality and morbidity among older adults. Currently, no pharmacological interventions have been specifically tailored to treat CH. OTUD7B (ovarian tumor domain-containing 7B) is a member of the ovarian tumor-related protease (OTU) family that regulates many important cell signaling pathways. However, the role of OTUD7B in the development of CH is unclear. Therefore, we investigated the role of OTUD7B in CH. METHODS AND RESULTS OTUD7B knockout mice were used to assay the role of OTUD7B in CH after transverse aortic coarctation surgery. We further assayed the specific functions of OTUD7B in isolated neonatal rat cardiomyocytes. We found that OTUD7B expression decreased in hypertrophic mice hearts and phenylephrine-stimulated neonatal rat cardiomyocytes. Furthermore, OTUD7B deficiency exacerbated transverse aortic coarctation surgery-induced myocardial hypertrophy, abnormal cardiac function, and fibrosis. In cardiac myocytes, OTUD7B knockdown promoted phenylephrine stimulation-induced myocardial hypertrophy, whereas OTUD7B overexpression had the opposite effect. An immunoprecipitation-mass spectrometry analysis showed that OTUD7B directly binds to KLF4 (Krüppel-like factor 4). Additional molecular experiments showed that OTUD7B impedes KLF4 degradation by inhibiting lysine residue at 48 site-linked ubiquitination and suppressing myocardial hypertrophy by activating the serine/threonine kinase pathway. CONCLUSIONS These results demonstrate that the OTUD7B-KLF4 axis is a novel molecular target for CH treatment.
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Affiliation(s)
- Bin‐Bin Du
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Jie‐Lei Zhang
- Department of EndocrinologyThe First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Ling‐Yao Kong
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Hui‐Ting Shi
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Dian‐Hong Zhang
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Xing Wang
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Chun‐Lei Yang
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Peng‐Cheng Li
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Rui Yao
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Cui Liang
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Lei‐Ming Wu
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
| | - Zhen Huang
- Cardiovascular Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou UniversityZhengzhouChina
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14
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Ni P, Pan K, Zhao B. Influence of N6-methyladenosine (m6A) modification on cell phenotype in Alzheimer's disease. PLoS One 2023; 18:e0289068. [PMID: 37549144 PMCID: PMC10406241 DOI: 10.1371/journal.pone.0289068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 07/11/2023] [Indexed: 08/09/2023] Open
Abstract
OBJECTIVE Recent research has suggested that m6A modification takes on critical significance to Neurodegeneration. As indicated by the genome-wide map of m6A mRNA, genes in Alzheimer's disease model achieved significant m6A methylation. This study aimed to investigate the hub gene and pathway of m6A modification in the pathogenesis of AD. Moreover, possible brain regions with higher gene expression levels and compounds exerting potential therapeutic effects were identified. Thus, this study can provide a novel idea to explore the treatment of AD. METHODS Differential expression genes (DEGs) of GSE5281 and GSE48350 from the Gene Expression Omnibus (GEO) database were screened using the Limma package. Next, the enrichment analysis was conducted on the screened DEGs. Moreover, the functional annotation was given for N6-methyladenosine (m6A) modification gene. The protein-protein interaction network (PPI) analysis and the visualization analysis were conducted using STRING and Cytoscape. The hub gene was identified using CytoHubba. The expression levels of Hub genes in different regions of brain tissue were analyzed based on Human Protein Atlas (HPA) database and Bgee database. Subsequently, the candidate drugs targeting hub genes were screened using cMAP. RESULTS A total of 42 m6A modified genes were identified in AD (20 up-regulated and 22 down-regulated genes). The above-described genes played a certain role in biological processes (e.g., retinoic acid, DNA damage response and cysteine-type endopeptidase activity), cellular components (e.g., mitochondrial protein complex), and molecular functions (e.g., RNA methyltransferase activity and ubiquitin protein ligase). KEGG results suggested that the above-mentioned genes were primarily involved in the Hippo signaling pathway of neurodegeneration disease. A total of 10 hub genes were screened using the protein-protein interaction network, and the expression of hub genes in different regions of human brain was studied. Furthermore, 10 compounds with potential therapeutic effects on AD were predicted. CONCLUSION This study revealed the potential role of the m6A modification gene in Alzheimer's disease through the bioinformatics analysis. The biological changes may be correlated with retinoic acid, DNA damage response and cysteine-type endopeptidase activity, which may occur through Hippo signaling pathway. The hub genes (SOX2, KLF4, ITGB4, CD44, MSX1, YAP1, AQP1, EGR2, YWHAZ and TFAP2C) and potential drugs may provide novel research directions for future prognosis and precise treatment.
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Affiliation(s)
- Pengyun Ni
- Department of Science and Education, Baoji Traditional Chinese Medicine Hospital, Baoji, Shannxi, P.R China
| | - Kaiting Pan
- Department of Neurology, Baoji Third Hospital, Baoji, Shannxi, P.R China
| | - Bingbing Zhao
- Emergency Department, Baoji Traditional Chinese Medicine Hospital, Baoji, Shannxi, P.R China
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15
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Ennerfelt H, Holliday C, Shapiro D, Zengeler K, Bolte A, Ulland T, Lukens J. CARD9 attenuates Aβ pathology and modifies microglial responses in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A 2023; 120:e2303760120. [PMID: 37276426 PMCID: PMC10268238 DOI: 10.1073/pnas.2303760120] [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: 03/08/2023] [Accepted: 04/04/2023] [Indexed: 06/07/2023] Open
Abstract
Recent advances have highlighted the importance of several innate immune receptors expressed by microglia in Alzheimer's disease (AD). In particular, mounting evidence from AD patients and experimental models indicates pivotal roles for TREM2, CD33, and CD22 in neurodegenerative disease progression. While there is growing interest in targeting these microglial receptors to treat AD, we still lack knowledge of the downstream signaling molecules used by these receptors to orchestrate immune responses in AD. Notably, TREM2, CD33, and CD22 have been described to influence signaling associated with the intracellular adaptor molecule CARD9 to mount downstream immune responses outside of the brain. However, the role of CARD9 in AD remains poorly understood. Here, we show that genetic ablation of CARD9 in the 5xFAD mouse model of AD results in exacerbated amyloid beta (Aβ) deposition, increased neuronal loss, worsened cognitive deficits, and alterations in microglial responses. We further show that pharmacological activation of CARD9 promotes improved clearance of Aβ deposits from the brains of 5xFAD mice. These results help to establish CARD9 as a key intracellular innate immune signaling molecule that regulates Aβ-mediated disease and microglial responses. Moreover, these findings suggest that targeting CARD9 might offer a strategy to improve Aβ clearance in AD.
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Affiliation(s)
- Hannah Ennerfelt
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA22908
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA22908
- Cell and Molecular Biology Graduate Training Program, University of Virginia, Charlottesville, VA22908
| | - Coco Holliday
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA22908
| | - Daniel A. Shapiro
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA22908
| | - Kristine E. Zengeler
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA22908
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA22908
- Cell and Molecular Biology Graduate Training Program, University of Virginia, Charlottesville, VA22908
| | - Ashley C. Bolte
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA22908
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA22908
- Medical Scientist Training Program, University of Virginia, Charlottesville, VA22908
| | - Tyler K. Ulland
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI53705
| | - John R. Lukens
- Department of Neuroscience, Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA22908
- Neuroscience Graduate Program, University of Virginia, Charlottesville, VA22908
- Cell and Molecular Biology Graduate Training Program, University of Virginia, Charlottesville, VA22908
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA22908
- Medical Scientist Training Program, University of Virginia, Charlottesville, VA22908
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16
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Jin LW, di Lucente J, Mendiola UR, Tang X, Zivkovic AM, Lebrilla CB, Maezawa I. The role of FUT8-catalyzed core fucosylation in Alzheimer's amyloid-β oligomer-induced activation of human microglia. Glia 2023; 71:1346-1359. [PMID: 36692036 PMCID: PMC11021125 DOI: 10.1002/glia.24345] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/03/2023] [Accepted: 01/10/2023] [Indexed: 01/25/2023]
Abstract
Fucosylation, especially core fucosylation of N-glycans catalyzed by α1-6 fucosyltransferase (fucosyltransferase 8 or FUT8), plays an important role in regulating the peripheral immune system and inflammation. However, its role in microglial activation is poorly understood. Here we used human induced pluripotent stem cells-derived microglia (hiMG) as a model to study the role of FUT8-catalyzed core fucosylation in amyloid-β oligomer (AβO)-induced microglial activation, in view of its significant relevance to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AβO and lipopolysaccharides (LPS) with a pattern of pro-inflammatory activation as well as enhanced core fucosylation and FUT8 expression within 24 h. Furthermore, we found increased FUT8 expression in both human AD brains and microglia isolated from 5xFAD mice, a model of AD-like cerebral amyloidosis. Inhibition of fucosylation in AβO-stimulated hiMG reduced the induction of pro-inflammatory cytokines, suppressed the activation of p38MAPK, and rectified phagocytic deficits. Specific inhibition of FUT8 by siRNA-mediated knockdown also reduced AβO-induced pro-inflammatory cytokines. We further showed that p53 binds to the two consensus binding sites in the Fut8 promoter, and that p53 knockdown abolished FUT8 overexpression in AβO-activated hiMG. Taken together, our evidence supports that FUT8-catalyzed core fucosylation is a signaling pathway required for AβO-induced microglia activation and that FUT8 is a component of the p53 signaling cascade regulating microglial behavior. Because microglia are a key driver of AD pathogenesis, our results suggest that microglial FUT8 could be an anti-inflammatory therapeutic target for AD.
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Affiliation(s)
- Lee-Way Jin
- Department of Pathology and Laboratory Medicine and M.I.N.D. Institute, University of California Davis Medical Center, 2805 50 Street, Sacramento, CA 95817
| | - Jacopo di Lucente
- Department of Pathology and Laboratory Medicine and M.I.N.D. Institute, University of California Davis Medical Center, 2805 50 Street, Sacramento, CA 95817
| | - Ulises R. Mendiola
- Department of Pathology and Laboratory Medicine and M.I.N.D. Institute, University of California Davis Medical Center, 2805 50 Street, Sacramento, CA 95817
| | - Xinyu Tang
- Department of Nutrition, University of California, Davis, CA 95618
| | | | | | - Izumi Maezawa
- Department of Pathology and Laboratory Medicine and M.I.N.D. Institute, University of California Davis Medical Center, 2805 50 Street, Sacramento, CA 95817
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17
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Sun Q, Xu W, Piao J, Su J, Ge T, Cui R, Yang W, Li B. Transcription factors are potential therapeutic targets in epilepsy. J Cell Mol Med 2022; 26:4875-4885. [PMID: 36065764 PMCID: PMC9549512 DOI: 10.1111/jcmm.17518] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022] Open
Abstract
Academics generally believe that imbalance between excitation and inhibition of the nervous system is the root cause of epilepsy. However, the aetiology of epilepsy is complex, and its pathogenesis remains unclear. Many studies have shown that epilepsy is closely related to genetic factors. Additionally, the involvement of a variety of tumour‐related transcription factors in the pathogenesis of epilepsy has been confirmed, which also confirms the heredity of epilepsy. In this review, we summarize the existing research on a variety of transcription factors and epilepsy and present relevant evidence related to transcription factors that may be targets in epilepsy. This information is of great significance for revealing the in‐depth molecular and cellular mechanisms of epilepsy.
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Affiliation(s)
- Qihan Sun
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Wenbo Xu
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Jingjing Piao
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Jingyun Su
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Tongtong Ge
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Wei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
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18
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You Z, Yang Z, Cao S, Deng S, Chen Y. The novel KLF4/BIG1 regulates LPS-mediated neuro-inflammation and migration in BV2 cells via PI3K/Akt/NF-kB signaling pathway. Neuroscience 2022; 488:102-111. [DOI: 10.1016/j.neuroscience.2022.01.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/26/2021] [Accepted: 01/18/2022] [Indexed: 12/17/2022]
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19
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Bu S, Lv Y, Liu Y, Qiao S, Wang H. Zinc Finger Proteins in Neuro-Related Diseases Progression. Front Neurosci 2021; 15:760567. [PMID: 34867169 PMCID: PMC8637543 DOI: 10.3389/fnins.2021.760567] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/11/2021] [Indexed: 01/02/2023] Open
Abstract
Zinc finger proteins (ZNF) are among the most abundant proteins in eukaryotic genomes. It contains several zinc finger domains that can selectively bind to certain DNA or RNA and associate with proteins, therefore, ZNF can regulate gene expression at the transcriptional and translational levels. In terms of neurological diseases, numerous studies have shown that many ZNF are associated with neurological diseases. The purpose of this review is to summarize the types and roles of ZNF in neuropsychiatric disorders. We will describe the structure and classification of ZNF, then focus on the pathophysiological role of ZNF in neuro-related diseases and summarize the mechanism of action of ZNF in neuro-related diseases.
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Affiliation(s)
- Siyuan Bu
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
| | - Yihan Lv
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
| | - Yusheng Liu
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
| | - Sen Qiao
- Department of Pharmacology, Center for Molecular Signaling (PZMS), School of Medicine, Saarland University, Homburg, Germany
| | - Hongmei Wang
- Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China
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20
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Bottero V, Alrafati F, Santiago JA, Potashkin JA. Transcriptomic and Network Meta-Analysis of Frontotemporal Dementias. Front Mol Neurosci 2021; 14:747798. [PMID: 34720873 PMCID: PMC8554122 DOI: 10.3389/fnmol.2021.747798] [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] [Received: 07/26/2021] [Accepted: 09/28/2021] [Indexed: 11/30/2022] Open
Abstract
Frontotemporal lobar degeneration (FTLD), also known as frontotemporal dementia (FTD), results in a progressive decline in executive function, leading to behavioral changes, speech problems, and movement disorders. FTD is the second most common cause of young-onset dementia affecting approximately 50–60,000 Americans. FTD exists in familial and sporadic forms, with GRN progranulin and C9orf72 mutations being the most common causes. In this study, we compared the sporadic and familial transcriptome within the cerebellum, frontal cortex, hippocampus, and Brodmann’s area 8 of patients with FTD to determine genes and pathways involved in the disease process. Most dysregulated genes expression occurred in the frontal cortex and Brodmann’s area 8 for genetic and sporadic forms of FTD, respectively. A meta-analysis revealed 50 genes and 95 genes are dysregulated in at least three brain regions in patients with familial mutations and sporadic FTD patients, respectively. Familial FTD genes centered on the Wnt signaling pathway, whereas genes associated with the sporadic form of FTD centered on MAPK signaling. The results reveal the similarities and differences between sporadic and familial FTD. In addition, valproic acid and additional therapeutic agents may be beneficial in treating patients with FTD.
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Affiliation(s)
- Virginie Bottero
- Center for Neurodegenerative Diseases and Therapeutics, Chicago Medical School, Discipline of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Fahed Alrafati
- Center for Neurodegenerative Diseases and Therapeutics, Chicago Medical School, Discipline of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | | | - Judith A Potashkin
- Center for Neurodegenerative Diseases and Therapeutics, Chicago Medical School, Discipline of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
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21
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Ding L, Xu X, Li C, Wang Y, Xia X, Zheng JC. Glutaminase in microglia: A novel regulator of neuroinflammation. Brain Behav Immun 2021; 92:139-156. [PMID: 33278560 DOI: 10.1016/j.bbi.2020.11.038] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 10/11/2020] [Accepted: 11/28/2020] [Indexed: 12/15/2022] Open
Abstract
Neuroinflammation is the inflammatory responses that are involved in the pathogenesis of most neurological disorders. Glutaminase (GLS) is the enzyme that catalyzes the hydrolysis of glutamine to produce glutamate. Besides its well-known role in cellular metabolism and excitatory neurotransmission, GLS has recently been increasingly noticed to be up-regulated in activated microglia under pathological conditions. Furthermore, GLS overexpression induces microglial activation, extracellular vesicle secretion, and neuroinflammatory microenvironment formation, which, are compromised by GLS inhibitors in vitro and in vivo. These results indicate that GLS has more complicated implications in brain disease etiology than what are previously known. In this review, we introduce GLS isoforms, expression patterns in the body and the brain, and expression/activities regulation. Next, we discuss the metabolic and neurotransmission functions of GLS. Afterwards, we summarize recent findings of GLS-mediated microglial activation and pro-inflammatory extracellular vesicle secretion, which, in turns, induces neuroinflammation. Lastly, we provide a comprehensive discussion for the involvement of microglial GLS in the pathogenesis of various neurological disorders, indicating microglial GLS as a promising target to treat these diseases.
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Affiliation(s)
- Lu Ding
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China
| | - Xiaonan Xu
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China
| | - Congcong Li
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China
| | - Yi Wang
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China; Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200434, China.
| | - Xiaohuan Xia
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China; Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200434, China.
| | - Jialin C Zheng
- Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200072, China; Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China; Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200434, China; Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5930, USA.
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Jiang Y, Gong H, Jiang S, She C, Cao Y. Multi-walled carbon nanotubes decrease neuronal NO synthase in 3D brain organoids. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 748:141384. [PMID: 32823226 DOI: 10.1016/j.scitotenv.2020.141384] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 06/11/2023]
Abstract
Multi-walled carbon nanotubes (MWCNTs) might induce the dysfunction of neuronal NO synthase (nNOS) and impair the function of brains. But to the best of our knowledge, this conclusion was made by using laboratory animals or conventional nerve cell cultures; however, these models might not reflect the complex conditions of human brains. Recently, the development of 3D brain organoids (also known as organotypic cultures) derived from human induced pluripotent stem cells (iPSCs) provides a platform to investigate the behaviors of human brains in vitro. In this study, we investigated the toxicity of MWCNTs to 3D brain organoids which expressed the cortical layer markers. It was shown that MWCNTs induced cytotoxicity to 3D brain organoids but not in dose-dependent manner. Exposure to high level of MWCNTs (64 μg/mL) reduced the levels of intracellular NO but increased superoxide. As the mechanism, 64 μg/mL MWCNTs significantly reduced the protein level of nNOS. The nNOS regulators nuclear factor kappa-B (NF-κB) proteins were significantly induced by MWCNTs, whereas Kruppel-like factor 4 (KLF4) proteins were reduced particularly after exposure to low level of MWCNTs (16 μg/mL). The results from fluorescence micro-optical sectioning tomography (MOST) confirmed the decrease of nNOS proteins, not only at the out-layers that directly contacted MWCNTs, but also at the inner-layers. Combined, our results suggested that MWCNTs could decrease nNOS activity by inducing oxidative stress and modulating NF-κB-KLF4 pathway. This study also showed the potential of 3D brain organoids in mechanism-based toxicology studies.
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Affiliation(s)
- Ying Jiang
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province and Key Laboratory of Hunan Higher Education for Western Hunan Medicinal Plant and Ethnobotany, Huaihua University, Huaihua 418008, China; Key Laboratory of Environment-Friendly Chemistry and Application of Ministry of Education, Lab of Biochemistry, College of Chemistry, Xiangtan University, Xiangtan 411105, China
| | - Housheng Gong
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province and Key Laboratory of Hunan Higher Education for Western Hunan Medicinal Plant and Ethnobotany, Huaihua University, Huaihua 418008, China; Key Laboratory of Environment-Friendly Chemistry and Application of Ministry of Education, Lab of Biochemistry, College of Chemistry, Xiangtan University, Xiangtan 411105, China
| | - Shaohua Jiang
- College of Materials Science and Engineering, Nanjing Forestry University, Nanjing 210037, China
| | - Chaowen She
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province and Key Laboratory of Hunan Higher Education for Western Hunan Medicinal Plant and Ethnobotany, Huaihua University, Huaihua 418008, China.
| | - Yi Cao
- Key Laboratory of Environment-Friendly Chemistry and Application of Ministry of Education, Lab of Biochemistry, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
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KLF4 Exerts Sedative Effects in Pentobarbital-Treated Mice. J Mol Neurosci 2020; 71:596-606. [PMID: 32789565 DOI: 10.1007/s12031-020-01680-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 08/05/2020] [Indexed: 10/23/2022]
Abstract
KLF4 is a zinc-finger transcription factor that plays an essential role in many biological processes, including neuroinflammation, neuron regeneration, cell proliferation, and apoptosis. Through effects on these processes, KLF4 has likely roles in Alzheimer's disease, Parkinson's disease, and traumatic brain injury. However, little is known about the role of KLF4 in more immediate behavioral processes that similarly depend upon broad changes in brain excitability, such as the sleep process. Here, behavioral approaches, western blot, and immunohistochemical experiments were used to explore the role of KLF4 on sedation and the potential mechanisms of those effects. The results showed that overexpression of KLF4 prolonged loss of righting reflex (LORR) duration in pentobarbital-treated mice and increased c-Fos expression in the lateral hypothalamus (LH) and the ventrolateral preoptic nucleus (VLPO), while it decreased c-Fos expression in the tuberomammillary nucleus (TMN). Moreover, overexpression of KLF4 reduced the expression of p53 in the hypothalamus and increased the expression of STAT3 in the hypothalamus. Therefore, these results suggest that KLF4 exerts sedative effects through the regulation of p53 and STAT3 expression, and it indicates a role of KLF4 ligands in the treatment of sleep disorders.
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Identification of a pro-elongation effect of diallyl disulfide, a major organosulfur compound in garlic oil, on microglial process. J Nutr Biochem 2020; 78:108323. [DOI: 10.1016/j.jnutbio.2019.108323] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 10/30/2019] [Accepted: 12/06/2019] [Indexed: 12/11/2022]
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Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders. Int J Mol Sci 2020; 21:ijms21062050. [PMID: 32192109 PMCID: PMC7139711 DOI: 10.3390/ijms21062050] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/11/2020] [Accepted: 03/14/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Methods: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. Results: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.
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Targeted Krüppel-Like Factor 4 Gene Knock-Out in Retinal Ganglion Cells Improves Visual Function in Multiple Sclerosis Mouse Model. eNeuro 2020; 7:ENEURO.0320-19.2020. [PMID: 32165410 PMCID: PMC7139550 DOI: 10.1523/eneuro.0320-19.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 02/12/2020] [Accepted: 02/20/2020] [Indexed: 12/26/2022] Open
Abstract
Axonal demyelination injury and neuronal degeneration are the primary causes of visual disability in multiple sclerosis (MS)-linked optic neuritis patients. Immunomodulatory therapies targeting inflammation have failed to avert the disease progression and no therapies exist to prevent the neuronal deficits seen in MS to date. Neuroprotective strategies targeting oligodendrocytes and astroglia have shown limited success due to a lack of axonal regeneration from injured neurons. In this study, we used the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS to investigate the axonal regenerative approach to improve the neuronal function. Our approach focused on targeted knock-out (KO) of the developmentally regulated axon growth inhibitory Krüppel-like factor 4 (Klf4) gene in retinal ganglion cells (RGCs) of Klf4fl/flmice by intravitreal delivery of AAV2-Cre-ires-EGFP recombinant virus (1) at the time of EAE sensitization and (2) after the onset of optic neuritis-mediated visual defects in the mice. Klf4 gene KO performed simultaneous with EAE sensitization prevented the visual loss as assessed by pattern electroretinograms (PERGs) in the mice and protected the RGCs from EAE-mediated death. More importantly, however, Klf4 gene KO after the onset of optic neuritis also resulted in RGC neuroprotection with additional restoration of their function, thereby improving the visual function outcomes in the EAE model. This study establishes the efficacy of Klf4 targeted knock-down in EAE even after the onset of disease symptoms, and thus should be further explored as a potential treatment strategy for MS/optic neuritis patients.
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27
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Ma N, Tie C, Yu B, Zhang W, Wan J. Identifying lncRNA-miRNA-mRNA networks to investigate Alzheimer's disease pathogenesis and therapy strategy. Aging (Albany NY) 2020; 12:2897-2920. [PMID: 32035423 PMCID: PMC7041741 DOI: 10.18632/aging.102785] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/19/2020] [Indexed: 12/23/2022]
Abstract
Alzheimer’s disease (AD), the most common cause of dementia, leads to neuronal damage and deterioration of cognitive functions in aging brains. There is evidence suggesting the participation of noncoding RNAs in AD-associated pathophysiology. A potential linkage between AD and lncRNA-associated competing endogenous RNA (ceRNA) networks has been revealed. Nevertheless, there are still no genome-wide studies which have identified the lncRNA-associated ceRNA pairs involved in AD. For this reason, deep RNA-sequencing was performed to systematically investigate lncRNA-associated ceRNA mechanisms in AD model mice (APP/PS1) brains. Our results identified 487, 89, and 3,025 significantly dysregulated lncRNAs, miRNAs, and mRNAs, respectively, and the most comprehensive lncRNA-associated ceRNA networks to date are constructed in the APP/PS1 brain. GO analysis revealed the involvement of the identified networks in regulating AD development from distinct origins, such as synapses and dendrites. Following rigorous selection, the lncRNA-associated ceRNA networks in this AD mouse model were found to be mainly involved in synaptic plasticity as well as memory (Akap5) and regulation of amyloid-β (Aβ)-induced neuroinflammation (Klf4). This study presents the first systematic dissection of lncRNA-associated ceRNA profiles in the APP/PS1 mouse brain. The identified lncRNA-associated ceRNA networks could provide insights that facilitate AD diagnosis and future treatment strategies.
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Affiliation(s)
- Nana Ma
- Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen 518000, Guangdong Province, China
| | - Changrui Tie
- Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen 518000, Guangdong Province, China
| | - Bo Yu
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen 518000, Guangdong Province, China.,Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen 518000, Guangdong Province, China
| | - Wei Zhang
- Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen 518000, Guangdong Province, China
| | - Jun Wan
- Shenzhen Key Laboratory for Neuronal Structural Biology, Biomedical Research Institute, Shenzhen Peking University - The Hong Kong University of Science and Technology Medical Center, Shenzhen 518000, Guangdong Province, China.,Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong 999077, China
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Rickert U, Cossais F, Heimke M, Arnold P, Preuße-Prange A, Wilms H, Lucius R. Anti-inflammatory properties of Honokiol in activated primary microglia and astrocytes. J Neuroimmunol 2018; 323:78-86. [DOI: 10.1016/j.jneuroim.2018.07.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 07/06/2018] [Accepted: 07/24/2018] [Indexed: 01/24/2023]
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29
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Cheng Z, Zou X, Jin Y, Gao S, Lv J, Li B, Cui R. The Role of KLF 4 in Alzheimer's Disease. Front Cell Neurosci 2018; 12:325. [PMID: 30297986 PMCID: PMC6160590 DOI: 10.3389/fncel.2018.00325] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 09/07/2018] [Indexed: 01/30/2023] Open
Abstract
Krüppel-like factor 4 (KLF4), a member of the family of zinc-finger transcription factors, is widely expressed in range of tissues that play multiple functions. Emerging evidence suggest KLF4’s critical regulatory effect on the neurophysiological and neuropathological processes of Alzheimer’s disease (AD), indicating that KLF4 might be a potential therapeutic target of neurodegenerative diseases. In this review, we will summarize relevant studies and illuminate the regulatory role of KLF4 in the neuroinflammation, neuronal apoptosis, axon regeneration and iron accumulation to clarify KLF4’s status in the pathogenesis of AD.
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Affiliation(s)
- Ziqian Cheng
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Xiaohan Zou
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Yang Jin
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Shuohui Gao
- Department of Orthopedics, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jiayin Lv
- Department of Gastrointestinal Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
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Qi Y, Ji XF, Chi TY, Liu P, Jin G, Xu Q, Jiao Q, Wang LH, Zou LB. Xanthoceraside attenuates amyloid β peptide 1-42-induced memory impairments by reducing neuroinflammatory responses in mice. Eur J Pharmacol 2017; 820:18-30. [PMID: 29229533 DOI: 10.1016/j.ejphar.2017.11.045] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 11/23/2017] [Accepted: 11/28/2017] [Indexed: 12/21/2022]
Abstract
Xanthoceraside, a novel triterpenoid saponin extracted from the husks of Xanthoceras sorbifolia Bunge, has neuroprotective effects in vivo and anti-inflammatory properties in vitro. However, the exact mechanism of xanthoceraside on anti-amyloid beta (Aβ)-induced neuroinflammatory responses has not been elucidated. Therefore, we used intracerebroventricular injection of amyloid 1-42 (Aβ1-42) to establish a mouse model to test the effects of xanthoceraside on Aβ-induced cognitive impairments and the TLR2/NF-κB and MAPK pathways. The mice received xanthoceraside (0.02, 0.08 or 0.32mg/kg) or vehicle from the day of Aβ1-42 injection. The Morris water maze test was performed 4 days after Aβ1-42 injection. The levels of inflammatory cytokines (interleukin (IL)-6 and IL-4) were measured by enzyme-linked immunosorbent assay (ELISA). The expression levels of glial fibrillary acidic protein (GFAP) and cluster of differentiation 11b (CD11b) in the hippocampus were determined with an immunohistochemistry assay. Inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) were analysed by Western blotting; iNOS, COX-2 and Toll-like receptor 2 (TLR2) mRNA expression levels were measured by reverse transcription-polymerase chain reaction (RT-PCR). Here, we observed that xanthoceraside at doses of 0.08 and 0.32mg/kg significantly improved learning and memory impairments and significantly inhibited GFAP and CD11b overexpression induced by Aβ1-42 in mice. ELISA results revealed that xanthoceraside suppressed IL-6 release and increased IL-4 levels. Western blotting results showed that xanthoceraside reduced iNOS and COX-2 protein levels in hippocampus; xanthoceraside also inhibited translocation of NF-κB p50 and p65 into the nucleus and phosphorylation of extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38. RT-PCR confirmed that xanthoceraside decreased iNOS, COX-2 and TLR2 mRNA levels. These results suggest that xanthoceraside inhibition of the TLR2 pathway and down-regulation of MAPK and NF-κB activities may be related to the improvement in learning and memory impairments.
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Affiliation(s)
- Yue Qi
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Department of Pharmacology, The Second Hospital Affiliated to Liaoning Chinese Medical University, Shenyang 110034, PR China
| | - Xue-Fei Ji
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Tian-Yan Chi
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Peng Liu
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Ge Jin
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Qian Xu
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Qing Jiao
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China
| | - Li-Hua Wang
- Shenyang Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang 110016, PR China
| | - Li-Bo Zou
- Department of Pharmacology, Life Science and Biopharmaceutics School, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
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