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

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

机构地区：[1]Institute of Neuroscience,School of Basic Medical Sciences,Chongqing Medical University,Chongqing,China [2]Department of Anatomy,Chongqing Medical University,Chongqing,China [3]Department of Physiology,Chongqing Medical University,Chongqing,China [4]Pediatric Research Institute,Children’s Hospital of Chongqing Medical University,Chongqing,China [5]Ministry of Education Key Laboratory of Child Development and Disorders,Children’s Hospital of Chongqing Medical University,Chongqing,China [6]National Clinical Research Center for Child Health and Disorders,Children’s Hospital of Chongqing Medical University,Chongqing,China [7]Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders,Children’s Hospital of Chongqing Medical University,Chongqing,China

出　　处：《Neural Regeneration Research》2025年第9期2633-2644,共12页中国神经再生研究（英文版）

基　　金：supported by the National Natural Science Foundation of China,No.82201582(to QT);Scientific and Technological Research Program of Chongqing Municipal Education Commission,No.KJQN202200457(to QT);General Project of Changqing Natural Science Foundation,No.cstc2021jcyjmsxmX0442(to ZL);CQMU Program for Youth Innovation in Future Medicine,No.W0044(to ZD and GH);Direct Research Project for PhD of Chongqing,No.CSTB2022BSXM-JCX0051(to ZL);the Project of the Top-Notch Talent Cultivation Program For the Graduate Students of Chongqing Medical University,No.BJRC202310(to CG)。

摘　　要：Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring 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 or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,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.

关 键 词：Alzheimer's disease amyloid-β APP/PS1 mice autophagy cognitive impairment histone deacetylase 6 lysosomal acidification microtubule acetylation valproic acid V-ATPASE 

分 类 号：R749.16[医药卫生—神经病学与精神病学]