A Novel Epigenetic Mechanism for Alzheimer's Disease

阿尔茨海默病的新表观遗传机制

• 批准号: 9890990
• 负责人: Zhen Yan
• 金额: $ 39.88万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890990
• 关键词: AMPA Receptors; Address; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein Precursor; Animal Model; Animals; Architecture; Area; Attention; Biological Assay; Brain Diseases; Brain region; Chromatin; Cognitive deficits; Complex; Data; Deacetylase; Disease; Disease Progression; Environmental Risk Factor; Enzymes; Epigenetic Process; Exhibits; Fibroblasts; Functional disorder; Gene Expression; Gene Mutation; Gene Silencing; Genes; Genetic Transcription; Genomic DNA; Glutamate Receptor; Glutamates; Goals; Histone Acetylation; Histone Deacetylase; Histones; Human; Human Amyloid Precursor Protein; Impaired cognition; Investigation; Lead; Learning; Link; MAPT gene; Mediating; Messenger RNA; Methyltransferase; Molecular; Mus; Mutation; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathology; Prefrontal Cortex; Presenile Alzheimer Dementia; Process; Promoter Regions; Proteins; Recovery; Research; Role; Senile Plaques; Short-Term Memory; Skin; Synapses; Testing; Therapeutic; Transgenic Mice; Work; base; chromatin remodeling; effective therapy; epigenetic regulation; executive function; familial Alzheimer disease; gene environment interaction; gene repression; genetic risk factor; hippocampal pyramidal neuron; histone acetyltransferase; histone methylation; histone methyltransferase; histone modification; human disease; human stem cells; induced pluripotent stem cell; inhibitor/antagonist; innovation; mouse model; mutant; neural circuit; novel; novel strategies; presenilin-1; stem cell differentiation; stem cell technology; synaptic function; transmission process; treatment strategy

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.

概括 该项目的主要目标是寻找阿尔茨海默病（AD）的新治疗策略，阿尔茨海默病是一种 一种毁灭性的神经退行性疾病，困扰着很多人，这是一种遗传风险的组合。 导致脆弱性基因放松管制的因素和环境因素可能与 AD 的发病机制被认为是 AD 表现的核心。 病理性基因改变，可能成为介导相关基因与环境相互作用的瓶颈 使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显着减弱 5xFAD 小鼠（5-6 个月）的皮质锥体神经元，伴随着 AMPA 和 此外，NMDA 受体转录和表达与抑制性组蛋白甲基化有关。 基因沉默，在 5xFAD 小鼠中显着升高。 由异常组蛋白甲基化引起的谷氨酸受体转录是突触和 AD 中的认知缺陷，靶向组蛋白甲基转移酶为 AD 提供了新的策略 为了检验这一假设，我们将解决三个具体目标 目标 1. 确定关键的表观遗传。 我们将研究导致 AD 小鼠模型中突触和认知缺陷的机制。 组蛋白甲基转移酶（HMT）和谷氨酸受体启动子区域的组蛋白甲基化 具有淀粉样斑块或神经原纤维缠结的 AD 小鼠模型 目的 2. 研究突触的拯救。 我们将研究是否可以通过针对 AD 小鼠模型中的关键表观遗传分子来改善和认知缺陷。 抑制抑制转录的常染色组蛋白甲基转移酶 EHMT1 和 EHMT2，可以 导致 AD 小鼠突触功能的恢复和认知障碍的改善。 目标 3。 研究来自 AD 患者的人类干细胞衍生神经元的分子改变和治疗策略。 找出 AD 小鼠模型中发现的表观遗传治疗策略是否也适用于 AD 对于患者，我们将利用创新的干细胞技术来检查人类神经元 我们将检查从皮肤成纤维细胞衍生的诱导多能干细胞（iPSC）的分化。 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 来自 AD 患者的研究，以及 EHMT1/2 抑制剂逆转突触缺陷的能力。 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 策略。