A Novel Epigenetic Mechanism for Alzheimer's Disease

摘要 这个项目的主要目标是找到阿尔茨海默病(AD)的新治疗策略， 毁灭性的神经退行性疾病折磨着大量的人。遗传风险的组合 导致脆弱基因放松管制的因素和环境因素可能与以下因素最相关 AD的发病机制。表观遗传机制被认为是其表现的中心。 病理性基因改变，可能成为调节相关基因-环境相互作用的瓶颈 导致疾病的发展。利用携带人类淀粉样蛋白5个家族性AD(5xFAD)突变的转基因小鼠 前体蛋白和早老素1，我们发现谷氨酸能传递在 5xFAD小鼠(5-6月龄)皮质锥体神经元，并伴有AMPA和AMPA的丢失 NMDA受体的转录和表达。此外，抑制性组蛋白甲基化与 基因沉默，在5xFAD小鼠中显著增加。我们假设异常的表观遗传调控 组蛋白异常甲基化导致的谷氨酸受体转录是突触和 AD的认知缺陷，靶向组蛋白甲基转移酶为AD提供了一种新的治疗策略 治疗。为了验证这一假设，我们将提出三个具体目标。目标1.确定关键的表观遗传学 导致阿尔茨海默病小鼠模型突触和认知缺陷的机制。我们将研究如何更改 谷氨酸受体启动子区的组蛋白甲基转移酶和组蛋白甲基化 有淀粉样斑块或神经原纤维缠结的AD小鼠模型。目的2.探讨突触的抢救 通过靶向AD小鼠模型中的关键表观遗传分子而导致认知缺陷。我们将研究是否 抑制常染色质的组蛋白甲基转移酶EHMT1和EHMT2可以抑制转录 促进AD小鼠突触功能的恢复和认知功能障碍的改善。目标3.至 研究阿尔茨海默病患者干细胞来源的神经元的分子变化和治疗策略。 为了找出在AD小鼠模型中发现的表观遗传治疗策略是否也适用于AD 患者，我们将利用创新的干细胞技术来检查人类神经元 分化自皮肤成纤维细胞的诱导多能干细胞(IPSC)。我们将研究 人类神经元谷氨酸受体转录和功能以及组蛋白甲基化的变化 以及EHMT1/2抑制剂逆转突触缺陷的能力。由此获得的结果 该项目将帮助确定特定疾病的表观遗传学特征并确定相应的治疗方法 应对AD的策略。

Summary The major goal of this project is to find out novel treatment strategies for Alzheimer’s disease (AD), a devastating neurodegenerative disorder afflicting a large number of people. A combination of genetic risk factors and environmental factors, which leads to deregulation of vulnerability genes, may be most relevant to the pathogenesis of AD. Eepigenetic mechanisms are suggested to be central to the manifestation of pathological gene alteration and might act as a bottleneck to mediate gene-environment interactions relevant to disease progression. Using the transgenic mice carrying 5 familial AD (5xFAD) mutations on human amyloid precursor protein and presenilin 1, we have found that glutamatergic transmission is significantly diminished in cortical pyramidal neurons of 5xFAD mice (5-6 months), which is accompanied by the loss of AMPA and NMDA receptor transcription and expression. Moreover, the repressive histone methylation, which is linked to gene silencing, is significantly elevated in 5xFAD mice. We hypothesize that abnormal epigenetic regulation of glutamate receptor transcription resulting from aberrant histone methylation underlies the synaptic and cognitive deficits in AD, and targeting the histone methyltransferases provides a novel strategy for AD treatment. To test this hypothesis, three specific aims will be addressed. Aim 1. To identify key epigenetic mechanisms causing the synaptic and cognitive deficits in AD mouse models. We will examine the alteration of histone methyltransferases (HMTs) and histone methylation at the promoter regions of glutamate receptors in AD mouse models with amyloid plaques or neurofibrillary tangles. Aim 2. To investigate the rescue of synaptic and cognitive deficits by targeting key epigenetic molecules in AD mouse models. We will examine whether inhibiting the euchromatic histone methyltransferases, EHMT1 and EHMT2, which repress transcription, could lead to the recovery of synaptic function and the amelioration of cognitive impairment in AD mice. Aim 3. To examine the molecular alteration and treatment strategy in human stem cell-derived neurons from AD patients. To find out whether the epigenetic treatment strategy found in AD mouse models might also work in AD patients, we will take advantage of the innovative stem-cell technology to examine human neurons differentiated from induced pluripotent stem cells (iPSC) derived from skin fibroblasts. We will examine the alterations of glutamate receptor transcription and function, as well as histone methylation, in human neurons from AD patients, and the capability of EHMT1/2 inhibitors to reverse synaptic deficits. Results gained from this project will help to define disease-specific epigenetic signatures and identify corresponding therapeutic strategies for AD.