低氧对阿尔茨海默病发病影响及表观遗传学机制研究

Alzheimer's disease (AD) is the most common neurodegenerative disease whose clinical manifestations appear in old age. Most cases of AD patients are late-onset, only 5-10% cases have family histroy. Research shows that most cases of AD arise through interactions between genetic and environmental factors. It is believed that hypoxia is an important environmental factor influencing the development of AD. Our group has previously demonstrated that hypoxia could increase β-amyloid (Aβ) generation in adult transgenic mice of AD. Recently, we have found that prenatal hypoxia exacerbated the cognitive impairment and cerebral Aβ-neuropathology on offspring mice. Interestingly, the wildtype offspring mice showed the similar phenotypes and pathology. Our previous studies have also shown that hypoxia could affect epigenetic regulation of certain AD-related gene expression. We have demonstrated that hypoxia treatment increased H3K9 methylation and decreased H3 acetylation at the NEP promoters, then down-regulated NEP expression in primary neurons. Based on the preliminary experiment results, in this project, we purpose to investigate whether hypoxia aggravate the AD-neuropathology in adult mice, and determine the underlying mechanism. We will study whether epigenetic regulation is associated with alteration of AD related genes in the hypoxic mice，focusing on DNA methylation and histone acetylation. We also plan to measure the expression level of DNA-methyltransferase to further explore the epigenetic intervention in AD progression resulting from adult hypoxia. Our research outcome will provide new evidence that hypoxia is a risk factor in AD, and early precaution may be beneficial to the individual who experiences hypoxic condition.

阿尔茨海默病(AD)是一种常见的神经退行性疾病，AD通常为散发性，家族性AD仅占5-10%左右，AD的发生与遗传因素和环境因素有关。遗传因素主要与APP、PS1和PS2等基因突变相关，环境因素中低氧是近期发现的重要的危险因子。我们先前研究证实低氧加重AD小鼠脑内AD病理,孕期低氧加剧子代AD小鼠学习记忆受损及脑内Aβ聚集。有趣的是子代野生型小鼠出现类似的病理表型。我们前期实验还发现，低氧改变NEP启动子组蛋白修饰而下调NEP表达，提示低氧通过表观遗传修饰调节基因表达。基于上述发现，本课题将研究低氧对AD发病的影响及其发生机制，验证低氧通过减少AD相关基因启动子区DNA甲基化水平而加剧Aβ聚集，并探讨早期表观遗传DNA甲基转移酶3a2基因治疗对AD发病的作用。本研究结果将进一步明确低氧是AD发生的危险因素及其作用机制，发现AD治疗新靶点，并为早期预防提供依据。

阿尔茨海默病（AD）是一种常见的神经退行性疾病，一般认为其发生是基因和环境因素共同作用的结果。近期研究表明，低氧作为AD重要的环境危险因素，与AD的病理变化密切相关。本课题在APPSwe/PS1dE9 AD转基因小鼠模型上发现慢性低氧加重小鼠的学习记忆能力损害，增加小鼠脑内Aβ水平、tau蛋白磷酸化，导致突出微结构变化等AD相关病理改变。明确了慢性低氧是AD发生发展的危险因素。在动物及细胞水平证明慢性可通过下调DNMT3b蛋白的表达降低γ分泌酶组分基因启动子区域CpG岛的甲基化水平，从而增加Aβ的生成，加重AD的病理变化。本课题还探讨了慢性低氧对小鼠脑内自噬水平的影响，发现慢性低氧可通过AMPK-mTOR通路诱导小鼠脑内自噬的激活。慢性低氧作为AD重要的环境危险因素，可能在AD的发生发展中发挥重要作用。