Supporting data for "Roles of DNA methylation on memory and serotonin neurotransmission in Alzheimer’s disease"

Alzheimer’s disease (AD) is becoming increasingly prevalent as the global population ages. Despite decades of research, the complex pathogenic mechanisms of AD remain largely elusive. In this thesis, the roles of hippocampal DNA methyltransferase 3a (DNMT3a) in mediating the pro-cognitive molecular changes of L-methionine (MET) were examined in 5xFAD mice by hippocampal specific knockdown of DNMT3a. It was shown that DNMT3a is necessary for MET-induced spatial memory enhancement, amyloid-β reduction, microgliosis reduction, and 5-HT fiber preservation in the hippocampus. Whether DNMT3a can modulate these processes independently from MET was further examined by hippocampal specific overexpression or knockdown of DNMT3a. Surprisingly, both manipulations were found to impair spatial memory, and such effects were seen in both wildtype and 5xFAD mice, suggesting that the physiological homeostasis of DNA methylation/demethylation processes is pivotal in normal memory functions. Moreover, overexpression and knockdown of DNMT3a were found to differentially affect amyloid-β deposition, microgliosis, and 5-HT neurotransmission in the hippocampus. Overall, findings in this thesis accentuated the important roles of DNA methylation in memory regulation in AD and established the brain 5-HT system as a viable target of DNA methylation modulating therapeutics for AD.

随着全球人口老龄化趋势的加剧，阿尔茨海默病（Alzheimer’s disease，AD）的发病率正日益攀升。尽管数十年的研究，阿尔茨海默病的复杂致病机制仍然难以捉摸。在本篇论文中，通过对5xFAD小鼠海马体中DNA甲基转移酶3a（hippocampal DNA methyltransferase 3a，DNMT3a）的特异性敲低，探讨了DNMT3a在介导L-蛋氨酸（L-methionine，MET）促认知分子变化中的作用。研究结果表明，DNMT3a对于MET诱导的空间记忆增强、β-淀粉样蛋白减少、小胶质细胞浸润减少以及海马体中5-HT纤维的保存是必需的。此外，通过海马体特异性过表达或敲低DNMT3a，进一步探讨了DNMT3a是否能够独立于MET调节这些过程。令人惊讶的是，这两种操作均被发现损害了空间记忆，且这种影响在野生型和5xFAD小鼠中均可见，这表明DNA甲基化/去甲基化过程的生理稳态在正常记忆功能中至关重要。此外，DNMT3a的过表达和敲低被发现能够差异性地影响海马体中的β-淀粉样蛋白沉积、小胶质细胞浸润和5-HT神经传递。总体而言，本论文强调了DNA甲基化在阿尔茨海默病记忆调节中的重要作用，并将大脑5-HT系统确立为DNA甲基化调节治疗阿尔茨海默病的潜在靶点。