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.
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)。
作者简介
Correspondence to:Qing Tang,PhD,tangqingzoe@cqmu.edu.cn,https://orcid.org/0000-0002-0946-7171;Correspondence to:Zhifang Dong,PhD,zfdong@aliyun.com,https://orcid.org/0000-0002-3411-7923;Correspondence to:Guiqiong He,PhD,guiqionghe@cqmu.edu.cn.https://orcid.org/0000-0002-7077-2001;Zhimin Long,These authors contributed equally to this work;Chuanhua Ge,These authors contributed equally to this work.
