Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (9): 2633-2644.doi: 10.4103/NRR.NRR-D-23-01633

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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

Zhimin Long1, 2, #, Chuanhua Ge1, 2, #, Yueyang Zhao1, 2, Yuanjie Liu1, 2, Qinghua Zeng1, 2, Qing Tang1, 3, *, Zhifang Dong4, 5, 6, 7, *, Guiqiong He1, 2, *   

  1. 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
  • Online:2025-09-15 Published:2024-12-30
  • Contact: Qing Tang, PhD, tangqingzoe@cqmu.edu.cn; Zhifang Dong, PhD, zfdong@aliyun.com; Guiqiong He, PhD, guiqionghe@cqmu.edu.cn.
  • Supported by:
    This study was 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 Chongqing 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).

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Abstract: 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 or thehistone 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.

Key words: Alzheimer’s disease,  amyloid-β,  APP/PS1 mice,  autophagy,  cognitive impairment,  histone deacetylase 6,  lysosomal acidification,   microtubule acetylation,  valproic acid,  V-ATPase