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MicroRNA-128 suppresses tau phosphorylation and reduces amyloid-beta accumulation by inhibiting the expression of GSK3β, APPBP2, and mTOR in Alzheimer's disease.

التفاصيل البيبلوغرافية
العنوان: MicroRNA-128 suppresses tau phosphorylation and reduces amyloid-beta accumulation by inhibiting the expression of GSK3β, APPBP2, and mTOR in Alzheimer's disease.
المؤلفون: Li S; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Poon CH; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Zhang Z; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.; The Brain Cognition and Brain Disease Institute (BCBDI), CAS Key Laboratory of Brain Connectome and Manipulation, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China., Yue M; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Chen R; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Zhang Y; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada., Hossain MF; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Pan Y; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Zhao J; Department of Clinical Immunology, Third Hospital of Sun Yat-sen University, Guangzhou, China., Rong L; Department of Medicine, The University of Hongkong-Shenzhen Hospital, Shenzhen, China., Chu LW; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China., Shea YF; Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China., Rogaeva E; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada., Tu J; The Brain Cognition and Brain Disease Institute (BCBDI), CAS Key Laboratory of Brain Connectome and Manipulation, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China., St George-Hyslop P; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada., Lim LW; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China., Song YQ; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.; The Brain Cognition and Brain Disease Institute (BCBDI), CAS Key Laboratory of Brain Connectome and Manipulation, Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.; Department of Medicine, The University of Hongkong-Shenzhen Hospital, Shenzhen, China.; The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
المصدر: CNS neuroscience & therapeutics [CNS Neurosci Ther] 2023 Jul; Vol. 29 (7), pp. 1848-1864. Date of Electronic Publication: 2023 Mar 07.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101473265 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1755-5949 (Electronic) Linking ISSN: 17555930 NLM ISO Abbreviation: CNS Neurosci Ther Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford, UK : Wiley-Blackwell, c2008-
مواضيع طبية MeSH: Alzheimer Disease*/metabolism , MicroRNAs*/metabolism, Mice ; Animals ; Phosphorylation ; Glycogen Synthase Kinase 3 beta ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Disease Models, Animal ; TOR Serine-Threonine Kinases/metabolism
مستخلص: Introduction and Aims: Alzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid-beta (Aβ) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and modulation of these miRNAs can influence the development of tau and Aβ pathology. The brain-specific miRNA miR-128, encoded by MIR128-1 and MIR128-2, is important for brain development and dysregulated in AD. In this study, the role of miR-128 in tau and Aβ pathology as well as the regulatory mechanism underlying its dysregulation were investigated.
Methods: The effect of miR-128 on tau phosphorylation and Aβ accumulation was examined in AD cellular models through miR-128 overexpression and inhibition. The therapeutic potential of miR-128 in AD mouse model was assessed by comparing phenotypes of 5XFAD mice administered with miR-128-expressing AAVs with 5XFAD mice administered with control AAVs. Phenotypes examined included behavior, plaque load, and protein expression. The regulatory factor of miR-128 transcription was identified through luciferase reporter assay and validated by siRNA knockdown and ChIP analysis.
Results: Both gain-of-function and loss-of-function studies in AD cellular models reveal that miR-128 represses tau phosphorylation and Aβ secretion. Subsequent investigations show that miR-128 directly inhibits the expression of tau phosphorylation kinase GSK3β and Aβ modulators APPBP2 and mTOR. Upregulation of miR-128 in the hippocampus of 5XFAD mice ameliorates learning and memory impairments, decreases plaque deposition, and enhances autophagic flux. We further demonstrated that C/EBPα transactivates MIR128-1 transcription, while both C/EBPα and miR-128 expression are inhibited by Aβ.
Conclusion: Our findings suggest that miR-128 suppresses AD pathogenesis, and could be a promising therapeutic target for AD. We also find a possible mechanism underlying the dysregulation of miR-128 in AD, in which Aβ reduces miR-128 expression by inhibiting C/EBPα.
(© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)
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فهرسة مساهمة: Keywords: Alzheimer's disease; C/EBPα; amyloid-beta accumulation; miR-128; tau phosphorylation
المشرفين على المادة: 0 (MicroRNAs)
EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
0 (Amyloid beta-Peptides)
0 (tau Proteins)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
0 (Mirn128 microRNA, mouse)
تواريخ الأحداث: Date Created: 20230307 Date Completed: 20230707 Latest Revision: 20230718
رمز التحديث: 20230718
مُعرف محوري في PubMed: PMC10324361
DOI: 10.1111/cns.14143
PMID: 36880288
قاعدة البيانات: MEDLINE
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