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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' 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

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.

项目摘要 我们提出了实验，以严格研究LNCRNA是否影响基因转录程序 海马应响应阿尔茨海默氏病（AD）病理学，而LNCRNA的潜力为 在治疗上利用以促进AD中的记忆弹性。 AD的进展涉及海马，大脑中基因转录程序的严重破坏 学习和记忆所需的区域。表观遗传干预措施以增强AD的记忆弹性是 可能的。但是，这不是很好理解基因转录的异常表观遗传控制如何贡献 与广告相关的内存定义。我们和其他人已经证明表观遗传染色质重塑 机制，例如组蛋白的翻译后修饰，DNA甲基化和非编码RNA至关重要 为了调节记忆形成期间海马中海马中的记忆 - 允许基因。目前， 关于长的非编码RNA（LNCRNA）在记忆形成中的作用的知识差距很大 在健康的大脑及其在与广告相关的记忆功能障碍中如何改变。我们的长期目标是研究 LNCRNA在细胞类型的特定方式中的作用，并确定这些强大的表观遗传调节剂如何影响 AD中的内存形成。我们的飞行员数据表明​​，Neat1在CA1的区域中过表达 Happ-J20广告模型的海马。此外，我们证明了在 Happ-J20 AD模型的海马的CA1区域CA1逆转了记忆障碍。试点研究 提出组蛋白甲基化机制与neat1过表达之间的密切关系 - J20 AD型号。基于这些初步结果，我们计划检查操纵Neat1在 海马并确定对广告相关记忆下降的影响。获得进一步的机械洞察力 Neat1介导的基因转录在AD小鼠模型的海马中，我们将使用最新的。 诸如单核RNA分离之类的方法，然后通过RNA测序和染色质分离 纯化以阐明我们的AD动物中与LNCRNA耦合的细胞类型特异性表观遗传机制 型号。我们的总体假设是Neat1有助于与广告相关的转录变化 海马细胞，海马功能以及对记忆功能障碍的脆弱性。我们的具体目标是 以下内容：特定目的1：检验以下假设：NEAT1影响海马中的AD病理；具体的 目标2：确定Hippocampus中AD响应基因转录程序的NEAT1必要性； 特定目的3：确定NEAT1在AD中恢复染色质的机制；和 特定目标4：测试海马Neat1失调是否有助于广告相关的内存 功能障碍。总的来说，这些研究将对关联的广告的治疗选择具有广泛的影响 认知能力下降。