Department of Medical Biochemistry, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-0811, Japan.
Int J Mol Sci. 2022 Aug 12;23(16):9027. doi: 10.3390/ijms23169027.
Alzheimer's disease (AD) is an age-related neurodegenerative disease that is characterized by irreversible memory loss and cognitive decline. The deposition of amyloid-β (Aβ), especially aggregation-prone Aβ, is considered to be an early event preceding neurodegeneration in AD. Sirtuins (SIRT1-7 in mammals) are nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases, and several sirtuins play important roles in AD. However, the involvement of SIRT7 in AD pathogenesis is not known. Here, we demonstrate that mRNA expression is increased in the cortex, entorhinal cortex, and prefrontal cortex of AD patients. We also found that Aβ treatment rapidly increased NADPH oxidase 4 (NOX4) expression at the post-transcriptional level, and induced reactive oxygen species (ROS) production and apoptosis in neuronal SH-SY5Y cells. In contrast, knockdown inhibited Aβ-induced ROS production and apoptosis by suppressing the upregulation of NOX4. Collectively, these findings suggest that the inhibition of SIRT7 may play a beneficial role in AD pathogenesis through the regulation of ROS production.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，其特征是不可逆转的记忆丧失和认知能力下降。淀粉样蛋白-β（Aβ）的沉积，特别是易于聚集的 Aβ，被认为是 AD 神经退行性变之前的早期事件。沉默信息调节因子 2 相关酶 7（SIRT7）是烟酰胺腺嘌呤二核苷酸依赖性赖氨酸去乙酰化酶/脱酰酶，几种 SIRT 在 AD 中发挥重要作用。然而，SIRT7 是否参与 AD 的发病机制尚不清楚。在这里，我们证明在 AD 患者的大脑皮层、内嗅皮层和前额叶皮层中，mRNA 的表达增加。我们还发现 Aβ 处理在转录后水平上迅速增加 NADPH 氧化酶 4（NOX4）的表达，并诱导神经元 SH-SY5Y 细胞中活性氧（ROS）的产生和凋亡。相比之下， 敲低通过抑制 NOX4 的上调抑制 Aβ诱导的 ROS 产生和凋亡。总的来说，这些发现表明抑制 SIRT7 可能通过调节 ROS 的产生在 AD 的发病机制中发挥有益作用。
