College of Basic Medical Science, Key Laboratory and Collaborative Innovation Center of Liaoning Province, China Medical University, Shenyang, Liaoning 110122, China; Health Sciences Institute, Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China.
College of Basic Medical Science, Key Laboratory and Collaborative Innovation Center of Liaoning Province, China Medical University, Shenyang, Liaoning 110122, China; Health Sciences Institute, Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang, Liaoning 110122, China.
Cell Rep. 2022 Jul 12;40(2):111062. doi: 10.1016/j.celrep.2022.111062.
Aging is a primary risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). SIRT2, an NAD(nicotinamide adenine dinucleotide)-dependent deacetylase, accumulates in the aging brain. Here, we report that, in the amyloid precursor protein (APP)/PS1 transgenic mouse model of AD, genetic deletion of SIRT2 or pharmacological inhibition of SIRT2 ameliorates cognitive impairment. We find that suppression of SIRT2 enhances acetylation of APP, which promotes non-amyloidogenic processing of APP at the cell surface, leading to increased soluble APP-α (sAPPα). We discover that lysines 132 and 134 of the major pathogenic protein β-amyloid (Aβ) precursor are acetylated and that these residues are deacetylated by SIRT2. Strikingly, exogenous expression of wild-type or an acetylation-mimic APP mutant protects cultured primary neurons from Aβ42 challenge. Our study identifies SIRT2-mediated deacetylation of APP on K132 and K134 as a regulated post-translational modification (PTM) and suggests inhibition of SIRT2 as a potential therapeutic strategy for AD.
衰老是神经退行性疾病（如阿尔茨海默病，AD）的主要风险因素。SIRT2 是一种依赖 NAD（烟酰胺腺嘌呤二核苷酸）的去乙酰化酶，在衰老的大脑中积累。在这里，我们报告在 AD 的 APP/PS1 转基因小鼠模型中，SIRT2 的基因缺失或 SIRT2 的药理学抑制可改善认知障碍。我们发现，抑制 SIRT2 增强了 APP 的乙酰化，这促进了 APP 在细胞表面的非淀粉样前体蛋白加工，导致可溶性 APP-α（sAPPα）增加。我们发现β-淀粉样蛋白（Aβ）前体的主要致病蛋白的赖氨酸 132 和 134 被乙酰化，这些残基被 SIRT2 去乙酰化。引人注目的是，野生型或乙酰化模拟 APP 突变体的外源性表达可保护培养的原代神经元免受 Aβ42 挑战。我们的研究确定 SIRT2 介导的 APP 上 K132 和 K134 的去乙酰化是一种受调控的翻译后修饰（PTM），并表明抑制 SIRT2 是 AD 的一种潜在治疗策略。
