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.

项目概要阿尔茨海默病 (AD) 是一种严重的痴呆症，影响着超过 500 万美国人，使其成为一种严重的痴呆症。 AD 患者表现出严重的进行性记忆障碍。目前的药物干预措施无法预防损失，并且发生的风险增加共病神经系统疾病，例如癫痫，缺乏有效的治疗和重症监护。晚期 AD 患者所需的治疗也给家庭和美国人带来了沉重的经济负担医疗保健系统：估计每年约 2000 亿美元。最近的研究表明，两者之间存在联系。一种特别相关的表观遗传修饰是 5-羟甲基胞嘧啶。 (5hmC) 在神经元中高度丰富，并在神经发育过程中受到动态调节。已在 AD 患者的大脑和小鼠 AD 模型中观察到 5hmC，这提高了可能性异常 DNA 5hmC 可能导致 AD 发病机制，GADD45A 介导 5hmC 的建立。 Gadd45a-/- 缺失小鼠在细胞中的表达能力下降，并且还具有 RNA 结合活性。海马长时程增强（LTP）和长期记忆和逆转学习受损，而野生型小鼠锥体兴奋性神经元中 Gadd45a 的过表达可增强 LTP 和记忆此外，我们的初步数据和公开的 RNA-seq 数据集表明 GADD45A。 AD 患者分离的神经元中 Gadd45a 表达下调，5hmC 水平也降低。在几种 AD 小鼠模型中（包括本提案中使用的 3xTG AD 模型）。观察结果表明，GADD45A 在神经功能和认知中发挥着重要作用通过 5hmC 水平的表观遗传调控以及随后基因表达的调节我们将通过比较 5hmC 水平和 Gadd45a-/- 之间的分布来检验目标 1 中的这一假设。我们还将对这些小鼠进行 RNA 测序和 ATAC 测序，以了解其功能。观察到的 5hmC 变化与基因表达和染色质可及性的特定改变有关。 Gadd45a 的过度表达增强了 LTP 和记忆巩固，我们发现 GADD45A 的上调对于 AD 具有治疗作用，因此，在目标 2 中，我们将检查是否具有治疗作用。在 AD 的 3xTG 小鼠模型中过度表达 Gadd45a 可以改善突触活性缺陷，改善学习和记忆，并减少自发性癫痫样放电。选择这些表型。因为它们代表了 AD 的重要病理特征，并且在认知方面与机械相关人们认为，神经过度兴奋会加速 AD 大脑的衰退。