A Novel Epigenetic Mechanism for Alzheimer's Disease

总结 该项目的主要目标是寻找阿尔茨海默病（AD）的新治疗策略， 一种严重的神经退行性疾病折磨着很多人遗传风险的组合 导致脆弱性基因失调的因素和环境因素可能与 AD的发病机制表观遗传机制被认为是中央的表现 病理性基因改变，并可能作为一个瓶颈，介导基因-环境相互作用相关 与疾病进展有关使用携带5个家族性AD（5xFAD）突变的转基因小鼠 前体蛋白和早老素1，我们已经发现， 5xFAD小鼠（5-6个月）的皮质锥体神经元，这伴随着AMPA和 NMDA受体转录和表达。此外，抑制性组蛋白甲基化，这是联系在一起， 在5xFAD小鼠中，基因沉默显著升高。我们假设， 由异常组蛋白甲基化引起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 治疗为了检验这一假设，将讨论三个具体目标。目标1。识别关键的表观遗传 导致AD小鼠模型中突触和认知缺陷的机制。我们将研究 组蛋白甲基转移酶（HMTs）和谷氨酸受体启动子区的组蛋白甲基化， 具有淀粉样斑块或神经纤维缠结的AD小鼠模型。目标二。为了研究突触的拯救 通过靶向AD小鼠模型中的关键表观遗传分子来治疗AD和认知缺陷。我们将研究是否 抑制常染色质组蛋白甲基转移酶EHMT 1和EHMT 2，它们抑制转录， 能恢复AD小鼠的突触功能，改善AD小鼠的认知障碍。目标3：到 研究AD患者的人类干细胞衍生神经元的分子改变和治疗策略。 为了确定在AD小鼠模型中发现的表观遗传治疗策略是否也适用于AD 我们将利用创新的干细胞技术来检查人类神经元 从源自皮肤成纤维细胞的诱导多能干细胞（iPSC）分化。我们会研究 人类神经元中谷氨酸受体转录和功能以及组蛋白甲基化的改变 以及EHMT 1/2抑制剂逆转突触缺陷的能力。由此获得的结果 该项目将有助于定义疾病特异性表观遗传特征，并确定相应的治疗方法。 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.