2. Academic Validation
  3. Enhanced autophagic clearance of amyloid-β via HDAC6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

Enhanced autophagic clearance of amyloid-β via HDAC6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

  • Neural Regen Res. 2024 Jul 10. doi: 10.4103/NRR.NRR-D-23-01633.
Zhimin Long 1 2,  Chuanhua Ge 1 2,  Yueyang Zhao 1 2,  Yuanjie Liu 1 2,  Qinghua Zeng 1 2,  Qing Tang 1 3,  Zhifang Dong 4 5 6 7,  Guiqiong He 1 2
Affiliations

Affiliations

  • 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.
PMID: 38993141 DOI: 10.4103/NRR.NRR-D-23-01633
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.

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