阿尔茨海默症 z-bo 2020-12-15 282

　　Under the guidance of Professor Le, Dr. Liu Hui and others have studied the effects of chronic hypoxia on the pathogenesis of Alzheimer's disease (AD) and focused on the mechanism of its occurrence from the perspective of epigenetics. As an important environmental factor, chronic hypoxia can affect the onset of AD at different stages of life. Previous research by Professor Le’s team confirmed that chronic hypoxia can aggravate the formation of senile plaques in the brains of AD mice, while chronic intermittent hypoxia during pregnancy can aggravate the impairment of learning and memory and the accumulation of senile plaques in the offspring of AD mice. Mice also have a similar pathological phenotype (Neurobiology of Aging 2009, 30: 1091-1098; 2013, 34: 663-678.). Moreover, hypoxia can change the histone modification of the NEP promoter and down-regulate the expression of NEP, thereby reducing the degradation of Aβ, suggesting that hypoxia can regulate gene expression through epigenetic modification.

　　 Based on the above findings, in this study, the author explored the effects of chronic hypoxia on the behavioral and AD-related neuropathological development of APPSwe/PS1dE9 transgenic mice, and further studied the possible mechanism of action from the perspective of DNA methylation modification. They found that compared with mice that have not undergone chronic hypoxia treatment, mice with chronic hypoxia showed a decrease in spatial learning and memory, and an aggravation of AD-related neuropathological phenotypes, including increased senile plaque formation, increased Aβ production, and Tau Increased protein phosphorylation and decreased synaptic vesicles; in addition, epigenetic analysis shows that chronic hypoxia reduces the level of genomic DNA methylation by reducing the expression of DNA methyltransferase 3b (DNMT3b) in the mouse brain , And down-regulate the methylation level of the promoter region of the γ-cutting enzyme component related genes (PS1, PEN2, NCT, etc.), thereby further affecting the expression of these genes at the protein level. Through epigenetic intervention, up-regulation of DNMT3b can reverse these changes. These findings indicate that chronic hypoxia may aggravate AD by down-regulating DNMT3b.

　　The results of the study have made it clear that chronic hypoxia is a risk factor for AD, and further clarified its molecular mechanism from the perspective of DNA methylation modification. The results not only support the view that environmental factors can stimulate and aggravate AD, but also provide new ideas for the treatment of AD and provide a theoretical basis for the early prevention of AD. In the future, by adjusting the epigenetic modification of organisms, it may provide a new breakthrough for the treatment of AD.