SIRT5 Represses Neurotrophic Pathways and Aβ Production in Alzheimer’s Disease by Targeting Autophagy,ACS Chemical Neuroscience

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SIRT5 Represses Neurotrophic Pathways and Aβ Production in Alzheimer’s Disease by Targeting Autophagy
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2021-11-17 , DOI: 10.1021/acschemneuro.1c00468
Shanshan Wu ₁ , Yafen Wei ₁ , Jingxin Li ₁ , Yan Bai ₂ , Ping Yin _{1,

2} , Shun Wang ₂

Affiliation

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in elderly individuals and characterized by impaired cognition and accumulation of β-amyloid (Aβ). Activating autophagy to clear Aβ is a plausible approach for AD treatment. The levels of Aβ and autophagy signaling factors in APP695/PS1-dE9 transgenic (APP/PS1) mice were detected by immuno histological analysis, real-time PCR, and the western blotting assay. The progression of AD was determined by Aβ levels, activated neurons (MAP2+), and microglia (Iba-1⁺). The learning ability was measured using a Morris water maze. Reactive oxygen species (ROS) production, malondialdehyde (MDA) levels, and mitochondrial superoxide dismutase (SOD) activity were checked to determine oxidative stress. AD mice exhibited impaired autophagy and a decreased level of SIRT5. SIRT5 overexpression promoted autophagy, manifested by elevated Becn1 and ratio of LC3b-II/I, as well as suppressed oxidative stress. The SIRT5-ameliorated neuron damage was correlated with suppressed activation of microglia and astrocytes. Elevated SIRT5 expression decreased the inflammation in AD brains and neurons. Inhibition of autophagy abolished the protective role of SIRT5 in neurons during AD. Our findings suggested that SIRT5 overexpression could ameliorate the progression of AD both in vitro and in vivo through activating autophagy. We presented ectopic expression of SIRT5 as a promising therapeutic approach for AD.

中文翻译：

SIRT5 通过靶向自噬抑制阿尔茨海默病中的神经营养途径和 Aβ 产生

阿尔茨海默病 (AD) 是老年人中最普遍的神经退行性疾病，其特征是认知受损和 β-淀粉样蛋白 (Aβ) 的积累。激活自噬以清除 Aβ 是一种可能的 AD 治疗方法。通过免疫组织学分析、实时荧光定量 PCR 和蛋白质印迹法检测 APP695/PS1-dE9 转基因 (APP/PS1) 小鼠中 Aβ 和自噬信号因子的水平。AD 的进展由 Aβ 水平、活化的神经元 (MAP2+) 和小胶质细胞 (Iba-1 ⁺）。使用莫里斯水迷宫测量学习能力。检查活性氧 (ROS) 产生、丙二醛 (MDA) 水平和线粒体超氧化物歧化酶 (SOD) 活性以确定氧化应激。AD 小鼠表现出自噬受损和 SIRT5 水平降低。SIRT5 过表达促进自噬，表现为 Becn1 和 LC3b-II/I 比值升高，以及抑制氧化应激。SIRT5 改善的神经元损伤与小胶质细胞和星形胶质细胞的抑制激活相关。升高的 SIRT5 表达降低了 AD 大脑和神经元的炎症。自噬的抑制消除了 SIRT5 在 AD 期间对神经元的保护作用。我们的研究结果表明 SIRT5 过表达可以改善 AD在体外和体外的进展在体内通过激活自噬。我们提出了 SIRT5 的异位表达作为一种有前途的 AD 治疗方法。

更新日期：2021-12-01

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