Exploring the role of GADD45A in Alzheimer's disease

探索 GADD45A 在阿尔茨海默病中的作用

基本信息

批准号：
10373344
负责人：
Andrew P Escayg
金额：
$ 41.61万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373344
关键词：
3xTg-AD mouse ATAC-seq Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient American Behavior Binding Proteins Biological Brain Cells Chromatin Clinical Cognition Cognitive Cognitive deficits DNA DNA Methylation Data Data Set Dementia Dioxygenases Economic Burden Epigenetic Process Epilepsy Exhibits Family GADD45A gene Gene Expression Genes Genetic Transcription Glutamate Receptor Goals Healthcare Systems Hippocampus (Brain)Impaired cognition Impairment Intensive Care Intervention Knockout Mice Learning Link Long-Term Potentiation Mediating Memory Memory Loss Messenger RNA Modification Molecular Mus Mutant Strains Mice N-Methylaspartate Nerve Degeneration Neurodegenerative Disorders Neurons Oxides Pathogenesis Pathologic Pathway interactions Patients Pharmacology Phenotype Play Proteins RNA Binding Regulation Reversal Learning Risk Role Synapses Synaptic plasticity Testing Therapeutic Transcript Translating Up-Regulation Wild Type Mouse base clinically relevant comorbidity effective therapy efficacious treatment epigenetic regulation excitatory neuron family burden gene repression genome-wide genomic locus improved long term memory memory consolidation mouse model mutant nervous system disorder neurodevelopment overexpression prevent recruit synaptic function transcriptome sequencing

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) is a severe form of dementia that affects over 5 million Americans, making it one of the most common neurodegenerative disorders. Patients with AD exhibit a severe form of progressive memory loss that cannot be prevented with current pharmacological interventions, and are at increased risk of developing comorbid neurological disorders such as epilepsy. The lack of efficacious treatments and the intensive care required for late-stage AD patients also places a significant economic burden on families and the American healthcare system: an estimated ~$200 billion annually. Recent studies have demonstrated a link between epigenetic modifications and AD. One epigenetic modification of particular relevance is 5-hydroxymethylcytosine (5hmC) which is highly enriched in neurons and is dynamically regulated during neurodevelopment. Alterations in 5hmC have been observed in the brains of patients with AD and in mouse AD models, raising the possibility that aberrant DNA 5hmC might contribute to AD pathogenesis. GADD45A mediates the establishment of 5hmC in cells and also possesses RNA binding activity. Interestingly, Gadd45a-/- null mice exhibit decreased hippocampal long-term potentiation (LTP) and impaired long-term memory and reversal learning, whereas overexpression of Gadd45a in pyramidal excitatory neurons of wild-type mice enhances LTP and memory consolidation. In addition, our preliminary data and publicly available RNA-seq data sets indicate that GADD45A is downregulated in neurons isolated from AD patients. Gadd45a expression and 5hmC levels are also reduced in several mouse models of AD (including the 3xTG AD model to be used in this proposal). Based on these observations, we hypothesize that GADD45A plays an important role in neuronal function and cognition through epigenetic regulation of 5hmC levels and subsequent modulation of gene expression in neurons. We will test this hypothesis in Aim 1 by comparing 5hmC levels and distribution between Gadd45a-/- null mutants and WT littermates. We will also perform RNA-seq and ATAC-seq on these mice to functionally relate observed changes in 5hmC with specific alterations in gene expression and chromatin accessibility. Given that overexpression of Gadd45a enhances LTP and memory consolidation, we hypothesize that upregulation of GADD45A will be therapeutic in AD. Therefore, in Aim 2, we will examine whether overexpression of Gadd45a in the 3xTG mouse model of AD can ameliorate deficits in synaptic activity, improve learning and memory, and reduce spontaneous epileptiform discharges. These phenotypes were selected because they represent important pathological features of AD and are mechanistically related since cognitive decline in the AD brain is believed to be accelerated by neuronal hyperexcitability.

项目摘要阿尔茨海默氏病（AD）是一种严重的痴呆形式，影响了超过500万美国人，使其成为最常见的神经退行性疾病。 AD患者暴露了严重的进行性记忆形式当前的药理干预措施无法预防的损失，并且有发展的风险合并症神经系统疾病，例如癫痫。缺乏有效的治疗和重症监护后期广告患者所需的人还对家庭和美国人造成了巨大的经济焚烧医疗保健系统：估计每年约2000亿美元。最近的研究表明表观遗传修饰和AD。特定相关性的一种表观遗传学修饰是5-羟基甲基胞嘧啶（5HMC）高度富集在神经上，并在神经发育过程中受动态调节。改变在5HMC中，在AD和小鼠AD模型的患者的大脑中观察到，增加了可能性这种异常的DNA 5HMC可能有助于AD发病机理。 GADD45A介导了5HMC的建立在细胞中，还具有RNA结合活性。有趣的是，gADD45A - / - 无效的小鼠暴露降低海马长期增强（LTP）和长期记忆和逆转学习损害野生型小鼠锥体兴奋性神经元中GADD45A的过表达增强了LTP和记忆力合并。此外，我们的初步数据和公开可用的RNA-seq数据集表明GADD45A 在AD患者分离的神经元中被下调。 GADD45A表达和5HMC水平也降低在AD的几种鼠标模型中（包括该提案中要使用的3XTG AD模型）。基于这些观察结果，我们假设GADD45A在神经元功能和认知中起重要作用通过对5HMC水平的表观遗传调节，并随后调节基因表达神经元。我们将通过比较GADD45A - / - 之间的5HMC水平和分布来检验AIM 1的假设。空突变体和wt同窝工人。我们还将在这些小鼠上执行RNA-SEQ和ATAC-SEQ 与观察到的5HMC发生变化与基因表达和染色质可及性的特定变化有关。给出 GADD45A的过表达增强了LTP和内存巩固，我们假设 GADD45A的上调将是AD中的理论。因此，在AIM 2中，我们将检查是否在AD的3XTG小鼠模型中，GADD45A的过表达可以改善突触活动的防御能力，改善学习和记忆，并减少赞助癫痫样排放。选择了这些表型因为它们代表了AD的重要病理特征，并且由于认知而机械地相关据信，AD大脑的下降被神经元过度兴奋性加速。