Epigenetic roles of DNA adenine methylation in Alzheimer's Disease

阿尔茨海默病（AD）是一种不可逆的、进行性的脑部疾病，其特征是记忆力逐渐下降， 语言和其他认知领域。AD是全世界老年人痴呆症的最常见原因， 但没有有效的治疗方法。衰老已被证明是AD的主要危险因素 发病越来越多的分子水平的证据表明，表观遗传调节，如化学修饰 调节特殊和时间基因表达的DNA分子，在衰老中起着重要作用 进展和AD发病机制。DNA腺嘌呤上的甲基化，N6-甲基腺嘌呤（6 mA）， 细菌基因组，最近在高等真核生物基因组中发现，包括哺乳动物。6 mA动态 在胚胎发育过程中受到调控，并在调控基因和转座子中发挥表观遗传作用 表情然而，6 mA的分子功能，特别是在大脑中，仍然在很大程度上未被探索。我们 初步研究强调，6 mA及其分子机制是正常神经发育所必需的， 果蝇的大脑因此，我们发现6 mA在出生后小鼠和人的大脑中存在着动态调节， 胚状体发育环境慢性应激诱导小鼠脑6 mA的动态变化， 与抑郁症高度相关的基因位点。重要的是，我们发现了6 mA的全局变化及其假定的 人类AD患者和AD小鼠模型脑中的分子机制。我们的数据强烈支持6 mA 作为一种因果机制，有助于AD发病机制。然而，很少有研究表明， 检查老化过程中脑区域特异性和神经元细胞类型特异性6 mA动力学， AD相关的改变。此外，缺乏关于6 mA甲基转移酶的知识（“作者”） 哺乳动物基因组中的6 mA及其结合蛋白（“阅读器”）限制了我们对6 mA依赖性 正常和患病大脑的表观遗传调节。此外，6 mA的表观遗传作用， 神经回路的兴奋/抑制平衡，其扰动与AD发病机制有关， 完全未被探索过基于这些数据，我们假设6 mA及其分子机制起着至关重要的作用， 在衰老中的作用及其失调有助于AD发病机制。我们将首先描绘6 mA的轮廓， 与衰老及其失调相关的各种脑区和兴奋性/抑制性神经元亚型 AD（目标1）。然后，我们将N6 amt 1的功能定义为6 mA甲基转移酶，并确定它们的作用 在兴奋性和抑制性神经元中的衰老和AD（目的2）。我们的数据表明，6 mA可能会拮抗 或分别募集缺氧诱导因子-1（Hif 1）和果蝇多梳（Pc）。基于这些结果， 我们将在神经元水平确定Hif 1和哺乳动物Polycomb蛋白在衰老和AD中的作用， 目标3（Aim 3）这项研究的结果将提供一个新的机制洞察疾病的病因，并有可能 发现具有重要临床和翻译意义的新分子靶点。

Alzheimer's disease (AD) is an irreversible, progressive brain disorder featuring gradual decline in memory, language and other areas of cognition. AD is the most common cause of dementia among the elderly worldwide, but no effective treatments are available. Aging has been demonstrated to be the primary risk factor for AD onset. Mounting evidence at the molecular level suggests epigenetic regulation, such as chemical modifications on DNA molecules that modulate special and temporal gene expression, plays fundamental roles in aging progression and AD pathogenesis. Methylation on the DNA adenine, N6-methyladenine (6mA) that enriched in the bacteria genome, was recently found in higher eukaryotic genomes, including mammals. 6mA is dynamically regulated during embryonic development and could play epigenetic roles in regulating gene and transposon expression. However, the molecular functions of 6mA, particularly in the brains, remain largely unexplored. Our preliminary study highlights that 6mA, and its molecular machinery, is required for proper neurodevelopment in Drosophila brains. Consistently, we found a dynamic regulation of 6mA during postnatal mouse brain and human embryoid body development. Environmental chronic stress induces dynamic alteration of 6mA in mouse brains, in the loci highly correlated with depression. Importantly, we found global alterations of 6mA and its putative molecular machinery in the brains of human AD patient and an AD mouse model. Our data strongly support 6mA serve as a causal mechanism to contribute to AD pathogenesis. However, there is little research precisely examining the brain region-specific and neuronal cell type-specific 6mA dynamics during aging progression and AD-associated alterations. Furthermore, the lack of knowledge regarding the 6mA methyltransferases (“writers”) and its binding proteins (“readers”) in the mammalian genome limits our understanding of 6mA-dependent epigenetic regulation in normal and diseased brains. Furthermore, the epigenetic roles of 6mA in excitation/inhibition balance of neural circuitries whose perturbation linked to AD pathogenesis remain completely unexplored. Based on these data, we hypothesize that 6mA and its molecular machinery play crucial roles in aging and their dysregulation contribute to AD pathogenesis. We will first delineate 6mA profiling in various brain regions and excitatory/inhibitory neuronal subtypes associated with aging and their dysregulation in AD (Aim 1). We will then define the functions of N6amt1 as a 6mA methyltransferase and determine their roles in aging and AD in excitatory and inhibitory neurons (Aim 2). Our data suggest 6mA could potentially antagonize or recruit hypoxia-induced factor-1 (Hif1) and Drosophila Polycomb (Pc), respectively. Based on these results, we will determine the roles of Hif1 and mammalian Polycomb proteins in aging and AD at the neuronal levels as well (Aim 3). Findings of this study will provide a novel mechanistic insight into disease etiology and are likely to discover new molecular targets with important clinical and translational implications.