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 我们提出实验来严格调查lncRNA是否影响基因转录程序， 海马对阿尔茨海默病（AD）病理学的反应，以及lncRNA被 在治疗上用于促进AD中的记忆弹性。 AD进展涉及海马体（大脑）中基因转录程序的深刻破坏 学习和记忆所必需的区域。增强AD记忆恢复力的表观遗传干预措施 可能然而，目前尚不清楚基因转录的异常表观遗传控制如何有助于 与AD相关的记忆缺陷我们和其他人已经证明，表观遗传染色质重塑 组蛋白的翻译后修饰、DNA甲基化和非编码RNA等机制至关重要 用于在记忆形成期间调节海马体中的记忆允许基因。现时 关于长链非编码RNA（lncRNA）在记忆形成中的作用， 在健康的大脑中，以及它在AD相关的记忆功能障碍中是如何改变的。我们的长期目标是研究 lncRNA在细胞类型特异性方式中的作用，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，Neat 1在海马CA 1区过表达。 来自hAPP-J20 AD模型的海马。此外，我们证明，抑制Neat 1的表达， hAPP-J20 AD模型的海马CA 1区逆转记忆损伤。试点研究还 提示hAPP中组蛋白甲基化机制与Neat 1过表达之间存在密切关系， J20 AD型号。基于这些初步的结果，我们计划研究操纵Neat 1在 海马和确定对AD相关记忆衰退的影响。为了进一步了解 Neat 1介导的AD小鼠模型海马区基因转录，我们将使用最先进的 方法如单核RNA分离，然后测序和染色质分离通过RNA 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 模型我们的总体假设是，Neat 1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。我们的具体目标是， 具体目的1：检验Neat 1影响海马中AD病理学的假设;具体目的1：检验Neat 1影响海马中AD病理学的假设。 目的2：探讨Neat 1在海马AD反应基因转录调控中的必要性; 具体目标3：确定Neat 1促进AD中染色质重组的机制;以及 具体目的4：测试海马Neat 1失调是否有助于AD相关记忆 功能障碍总的来说，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