A Novel Epigenetic Mechanism for Alzheimer's Disease

阿尔茨海默病的新表观遗传机制

基本信息

批准号：
10361607
负责人：
Zhen Yan
金额：
$ 6.27万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-10-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361607
关键词：
AMPA Receptors Address Age Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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的是找出针对阿尔茨海默氏病（AD）的新型治疗策略，灾难性的神经退行性疾病困扰着许多人。遗传风险的结合导致脆弱基因放松管制的因素和环境因素可能与 AD的发病机理。建议的机制被认为是表现的核心病理基因的改变，可能是介导基因环境相互作用相关的瓶颈疾病进展。使用携带5个家族AD（5xFAD）突变的转基因小鼠前体蛋白质和寄生虫1，我们发现谷氨酸能传播在 5XFAD小鼠的皮质金字塔神经元（5-6个月），这是通过损失AMPA和 NMDA受体转录和表达。此外，反射性组蛋白甲基化，与 5xFAD小鼠的基因沉默，显着升高。我们假设异常表观遗传调节异常组蛋白甲基化引起的谷氨酸受体转录是突触和认知在AD中定义，靶向组蛋白甲基转移酶为AD提供了一种新的策略治疗。为了检验这一假设，将解决三个具体目标。目标1。识别关键表观遗传学在AD小鼠模型中引起突触和认知缺陷的机制。我们将研究的改变 Hisstone甲基转移酶（HMTS）和Hisstone甲基化在谷氨酸受体的启动子区域中带有淀粉样蛋白斑块或神经纤维缠结的AD小鼠模型。目的2。调查突触的营救认知通过靶向AD小鼠模型中的关键表观遗传分子来定义。我们将检查是否抑制构型组蛋白甲基转移酶EHMT1和EHMT2（反映转录）可以导致突触功能的恢复和AD小鼠认知障碍的改善。目标3 检查AD患者的人类干细胞衍生神经元中的分子改变和治疗策略。找出AD鼠标模型中发现的表观遗传治疗策略是否也可能在AD中起作用患者，我们将利用创新的干细胞技术来检查人类神经元与源自皮肤成纤维细胞的诱导多能干细胞（IPSC）区分开。我们将检查人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患者以及EHMT1/2抑制剂逆转合成缺陷的能力。从中获得的结果项目将有助于定义疾病特异性的表观遗传学特征并确定相应的疗法广告策略。