The role of IncRNA Neat1 in Alzheimer's disease and related memory deficits

IncRNA Neat1 在阿尔茨海默病和相关记忆缺陷中的作用

基本信息

批准号：
10666025
负责人：
Farah Dominique Lubin
金额：
$ 65.71万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666025
关键词：
3xTg-AD mouse Age Age Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Animal Disease Models Area Astrocytes Brain Brain region Cell Nucleus Cell Separation Cells Chromatin Coupled DNA Methylation Data Data Set Disease Progression Dorsal Endocytosis Enzymes Epigenetic Process Fluorescent in Situ Hybridization Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Heterozygote Hippocampus Histones Homozygote Impaired cognition In Vitro Intervention J20 mouse Knock-in Knowledge Learning Magnetism Mammals Mass Spectrum Analysis Mediating Memory Memory Loss Memory impairment Neurons Pathogenesis Pilot Projects Play Post-Translational Protein Processing Proteins RNA RNA purification Regulation Regulator Genes Research Role Small Interfering RNA Testing Therapeutic Transgenic Organisms Untranslated RNA Vimentin astrogliosis cell type chromatin isolation by RNA purification sequencing chromatin remodeling epitranscriptome experimental study hippocampal pyramidal neuron histone methylation histone methyltransferase histone modification human disease immunoreactivity improved in silico insight knock-down long term memory mouse model mutant normal aging novel overexpression permissiveness programs promoter recruit resilience response sex small hairpin RNA tau-1

项目摘要

Project Summary We propose experiments to rigorously investigate whether lncRNAs influence gene transcription programs in the hippocampus in response to Alzheimer’s disease (AD) pathology, and the potential of lncRNAs to be therapeutically leveraged to promote memory resiliency in AD. AD progression involves profound disruptions in gene transcriptional programs in the hippocampus, the brain region necessary for learning and memory. Epigenetic interventions to enhance memory resilience in AD are possible. However, it is not well-understood how abnormal epigenetic control of gene transcription contributes to AD-related memory deficits. We and others have demonstrated that epigenetic chromatin remodeling mechanisms, like posttranslational modifications of histones, DNA methylation, and non-coding RNAs are crucial for the regulation of memory-permissive genes in the hippocampus during memory formation. Currently, a significant gap in knowledge exists regarding the role of long non-coding RNAs (lncRNAs) in memory formation in the healthy brain and how it is altered in AD-related memory dysfunction. Our long-term goal is to study the role of lncRNAs in a cell-type specific manner and to identify how these powerful epigenetic regulators impact memory formation in AD. Our pilot data demonstrate that Neat1 is overexpressed in area CA1 of the hippocampus from the hAPP-J20 AD model. Furthermore, we demonstrate that inhibiting Neat1 expression in area CA1 of the hippocampus of the hAPP-J20 AD model reverses memory impairments. Pilot studies also suggest a strong relationship between histone methylation mechanisms with Neat1 overexpression in the hAPP- J20 AD model. Based on these preliminary results, we plan to examine the effects of manipulating Neat1 in the hippocampus and determine effects on AD-related memory decline. To gain further mechanistic insight into Neat1 mediated gene transcription in the hippocampus of AD mouse models, we will use state-of-the-art approaches such as single nuclei RNA isolation followed by sequencing and Chromatin Isolation by RNA Purification to elucidate the cell-type specific epigenetic mechanisms coupled to lncRNAs in our AD animal models. Our overarching hypothesis is that Neat1 contributes to AD-associated transcriptional changes in hippocampal cells, hippocampal function, and vulnerability to memory dysfunction. Our Specific Aims are as follows: Specific Aim 1: Test the hypothesis that Neat1 impacts AD pathology in the hippocampus; Specific Aim 2: To determine the necessity of Neat1 on AD responsive gene transcription programs in the hippocampus; Specific Aim 3: To identify the mechanisms by which Neat1 contributes to chromatin restructuring in AD; and Specific Aim 4: To test whether hippocampal Neat1 dysregulation contributes to AD-related memory dysfunction. Collectively, these studies will have broad implications for treatment options for AD associated cognitive decline.

项目概要我们提出实验来严格研究 lncRNA 是否影响基因转录程序海马对阿尔茨海默病 (AD) 病理的反应，以及 lncRNA 的潜力治疗上可用于促进 AD 患者的记忆弹性。 AD 的进展涉及海马体（大脑）基因转录程序的严重破坏增强 AD 记忆恢复能力的学习和记忆所需的表观遗传干预区域。然而，目前尚不清楚基因转录的异常表观遗传控制如何发挥作用。我们和其他人已经证明表观遗传染色质重塑。组蛋白翻译后修饰、DNA 甲基化和非编码 RNA 等机制至关重要在记忆形成过程中调节海马体中的记忆许可基因。关于长非编码 RNA (lncRNA) 在记忆形成中的作用，存在显着的知识差距我们的长期目标是研究健康大脑中的变化以及 AD 相关记忆功能障碍中的变化。 lncRNA 以细胞类型特定方式发挥的作用，并确定这些强大的表观遗传调节因子如何影响 AD 中的记忆形成。我们的试验数据表明 Neat1 在 AD 的 CA1 区过度表达。此外，我们还证明了 hAPP-J20 AD 模型中 Neat1 表达的抑制。 hAPP-J20 AD 模型的海马 CA1 区也可逆转记忆障碍。表明组蛋白甲基化机制与 hAPP-Neat1 过表达之间存在密切关系基于这些初步结果，我们计划检查在 J20 AD 模型中操纵 Neat1 的效果。并确定对 AD 相关记忆衰退的影响，以进一步了解其机制。 Neat1 介导 AD 小鼠模型海马中的基因转录，我们将使用最先进的诸如单核 RNA 分离、随后测序和 RNA 染色质分离等方法纯化以阐明 AD 动物中与 lncRNA 偶联的细胞类型特异性表观遗传机制我们的总体假设是 Neat1 有助于 AD 相关的转录变化。海马细胞、海马功能和记忆功能障碍的脆弱性如下。具体目标 1：检验 Neat1 影响海马 AD 病理的假设；目标2：确定Neat1对海马AD反应基因转录程序的必要性；具体目标 3：确定 Neat1 促进 AD 和染色质重组的机制；具体目标 4：测试海马 Neat1 失调是否会导致 AD 相关记忆总的来说，这些研究将对 AD 相关的治疗选择产生广泛的影响。认知能力下降。