Cheng Rong, Bai Ning, Liu Shuhui, Zhao Xiong, Jiang Bo, Guo Wendong, Cao Sunrun, Liu Jingwei, Li Na, Li Xiaoman, Wu Xuan, Yi Fei, Wang Zhuo, Guo Qiqiang, Wei Jiayi, Bai Ming, Jiang Xiaoyou, Song Xiaoyu, Wang Zhuo, Miao Qi, Wang Difei, Di Yu, Liu Hua, Cao Liu
College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning 110122, China.
Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning 110122, China.
Sci Signal. 2024 Dec 10;17(866):eado1035. doi: 10.1126/scisignal.ado1035.
Alzheimer's disease (AD) is an aging-related neurodegenerative disorder that results in progressively impaired memory and is often associated with amyloid plaques. Previous studies implicate the deacetylases SIRT1 and SIRT2 in regulating the processing of amyloid precursor protein (APP). Here, we investigated whether APP is regulated by the related deacetylase SIRT6, which shows aging-associated decreases in activity. We found that the abundance of SIRT6 was reduced in the cortex and hippocampus of aged and AD model mice and negatively correlated with that of APP. In mouse hippocampal neurons and transfected human cells, SIRT6 interacted with and deacetylated APP at three consecutive Lys residues (Lys, Lys, and Lys). This deacetylation, in turn, increased the ubiquitylation of APP, leading to its proteasomal degradation. SIRT6 abundance in neurons was reduced by oxidative stress and DNA damage, both of which are implicated in neurodegenerative pathology. Systemic pharmacological activation of SIRT6 ameliorated both amyloid pathology and cognitive deficits in APP/PS1 mice, a mouse model of AD. The findings demonstrate that the activity of SIRT6 destabilizes APP and suggest that activating SIRT6 has therapeutic potential to reduce amyloid-associated pathology in patients with AD.
阿尔茨海默病（AD）是一种与衰老相关的神经退行性疾病，会导致记忆力逐渐受损，且常与淀粉样斑块有关。先前的研究表明去乙酰化酶SIRT1和SIRT2参与调节淀粉样前体蛋白（APP）的加工过程。在此，我们研究了APP是否受相关去乙酰化酶SIRT6的调节，SIRT6的活性会随着衰老而降低。我们发现，在老年小鼠和AD模型小鼠的皮质和海马体中，SIRT6的丰度降低，且与APP的丰度呈负相关。在小鼠海马神经元和转染的人类细胞中，SIRT6与APP在三个连续的赖氨酸残基（赖氨酸、赖氨酸和赖氨酸）处相互作用并使其去乙酰化。这种去乙酰化反过来又增加了APP的泛素化，导致其通过蛋白酶体降解。氧化应激和DNA损伤会降低神经元中SIRT6的丰度，而这两者都与神经退行性病变有关。SIRT6的全身药理学激活改善了APP/PS1小鼠（一种AD小鼠模型）的淀粉样病变和认知缺陷。这些发现表明，SIRT6的活性会使APP不稳定，并提示激活SIRT6具有降低AD患者淀粉样相关病变的治疗潜力。
