Enhanced autophagic clearance of amyloid-β via histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

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外文摘要：Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-β in neurons,which is a key step in senile plaque formation.Therefore,restoring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA orthehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Furthermore,we found that treatment with valproic acid markedly enhanced autophagy,promoted clearance of amyloid-β aggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

外文关键词：

Alzheimer's diseaseamyloid-βAPP/PS1 miceautophagycognitive impairmenthistone deacetylase 6lysosomal acidificationmicrotubule acetylationvalproic acidV-ATPase

作者：

Zhimin Long、Chuanhua Ge、Yueyang Zhao、Yuanjie Liu、Qinghua Zeng、Qing Tang、Zhifang Dong、Guiqiong He

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作者单位：

Institute of Neuroscience,School of Basic Medical Sciences,Chongqing Medical University,Chongqing,China

Department of Anatomy,Chongqing Medical University,Chongqing,China

Department of Physiology,Chongqing Medical University,Chongqing,China

Pediatric Research Institute,Children's Hospital of Chongqing Medical University,Chongqing,China

Ministry of Education Key Laboratory of Child Development and Disorders,Children's Hospital of Chongqing Medical University,Chongqing,China

National Clinical Research Center for Child Health and Disorders,Children's Hospital of Chongqing Medical University,Chongqing,China

Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders,Children's Hospital of Chongqing Medical University,Chongqing,China

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出版年：

2025

DOI：

10.4103/NRR.NRR-D-23-01633

中国神经再生研究(英文版)

中国康复医学会

中国神经再生研究(英文版)

影响因子：0.902

ISSN：1673-5374

年,卷(期)：2025.20(9)