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.

IF 5.9 2区 医学 Q2 CELL BIOLOGY Neural Regeneration Research Pub Date : 2025-09-01 Epub Date: 2024-07-10 DOI:10.4103/NRR.NRR-D-23-01633
Zhimin Long, Chuanhua Ge, Yueyang Zhao, Yuanjie Liu, Qinghua Zeng, Qing Tang, Zhifang Dong, Guiqiong He
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Abstract

JOURNAL/nrgr/04.03/01300535-202509000-00025/figure1/v/2024-11-05T132919Z/r/image-tiff 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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通过 HDAC6 介导的 V-ATP 酶组装和溶酶体酸化增强淀粉样蛋白-β的自噬清除,可在体外和体内预防阿尔茨海默病。
摘要:最近的研究表明,溶酶体的异常酸化会诱导神经元中淀粉样蛋白-β的自噬积累,这是老年斑形成的关键步骤。因此,恢复正常的溶酶体功能和重新平衡脑内神经元的溶酶体酸化可能是治疗阿尔茨海默病的一种新策略。微管乙酰化/脱乙酰化在溶酶体酸化中起着核心作用。在这里,我们发现用组蛋白去乙酰化酶6 shRNA或组蛋白去乙酰化酶6抑制剂丙戊酸抑制经典的微管去乙酰化酶,可通过调节V-ATP酶的组装促进阿尔茨海默病溶酶体的再酸化。此外,我们还发现丙戊酸能显著增强自噬作用,促进淀粉样蛋白-β聚集体的清除,并改善阿尔茨海默病小鼠模型的认知障碍。我们的研究结果证明了阿尔茨海默病中一种以前未知的神经保护机制,即丙戊酸抑制组蛋白去乙酰化酶6可增加V-ATP酶的装配和溶酶体酸化。
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来源期刊
Neural Regeneration Research
Neural Regeneration Research CELL BIOLOGY-NEUROSCIENCES
CiteScore
8.00
自引率
9.80%
发文量
515
审稿时长
1.0 months
期刊介绍: Neural Regeneration Research (NRR) is the Open Access journal specializing in neural regeneration and indexed by SCI-E and PubMed. The journal is committed to publishing articles on basic pathobiology of injury, repair and protection to the nervous system, while considering preclinical and clinical trials targeted at improving traumatically injuried patients and patients with neurodegenerative diseases.
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