Department of Gerontology and Geriatrics, Shengjing Hospital, China Medical University, Shenyang, China.
The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, China.
Aging Cell. 2023 Oct;22(10):e13967. doi: 10.1111/acel.13967. Epub 2023 Aug 21.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by amyloid-β (Aβ) deposition and neurofibrillary tangles. Although the NAD -dependent deacetylases SIRT1 and SIRT2 play pivotal roles in age-related diseases, their cooperative effects in AD have not yet been elucidated. Here, we report that the SIRT2:SIRT1 ratio is elevated in the brains of aging mice and in the AD mouse models. In HT22 mouse hippocampal neuronal cells, Aβ challenge correlates with decreased SIRT1 expression, while SIRT2 expression is increased. Overexpression of SIRT1 prevents Aβ-induced neurotoxicity. We find that SIRT1 impedes SIRT2-mediated APP deacetylation by inhibiting the binding of SIRT2 to APP. Deletion of SIRT1 reduces APP recycling back to the cell surface and promotes APP transiting toward the endosome, thus contributing to the amyloidogenic processing of APP. Our findings define a mechanism for neuroprotection by SIRT1 through suppression of SIRT2 deacetylation, and provide a promising avenue for therapeutic intervention of AD.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是淀粉样蛋白-β（Aβ）沉积和神经纤维缠结。尽管 NAD 依赖性去乙酰化酶 SIRT1 和 SIRT2 在与年龄相关的疾病中发挥着关键作用，但它们在 AD 中的协同作用尚未阐明。在这里，我们报告说，SIRT2：SIRT1 比率在衰老小鼠和 AD 小鼠模型的大脑中升高。在 HT22 小鼠海马神经元细胞中，Aβ 挑战与 SIRT1 表达降低相关，而 SIRT2 表达增加。SIRT1 的过表达可预防 Aβ 诱导的神经毒性。我们发现 SIRT1 通过抑制 SIRT2 与 APP 的结合来阻碍 SIRT2 介导的 APP 去乙酰化。SIRT1 的缺失减少了 APP 回收到细胞表面的循环，并促进了 APP 向内涵体的转运，从而有助于 APP 的淀粉样蛋白形成加工。我们的研究结果定义了 SIRT1 通过抑制 SIRT2 去乙酰化来实现神经保护的机制，并为 AD 的治疗干预提供了有希望的途径。
