REST and Neural Network Dysfunction in Alzheimer's Disease

阿尔茨海默病中的休息和神经网络功能障碍

• 批准号: 10229122
• 负责人: Bruce A YANKNER
• 金额: $ 62.64万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229122
• 关键词: ATAC-seq; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid deposition; Applications Grants; Biological Models; Biology; Brain; Cells; Cerebrum; Chromatin; Cognitive; Complement; Electric Stimulation; Electrophysiology (science); Failure; Gene Expression; Genes; Genomics; Goals; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Interneurons; Intervention; Knock-out; Knockout Mice; Longevity; LoxP-flanked allele; Maps; Memory; Memory Loss; Methods; Modeling; Neural Pathways; Neurons; Organoids; Pathology; Patients; Play; Regulation; Research Personnel; Role; Synaptic plasticity; Transgenic Organisms; aging brain; apolipoprotein E-4; entorhinal cortex; gene discovery; in vivo; induced pluripotent stem cell; interdisciplinary approach; knockout gene; loss of function; mild cognitive impairment; mouse model; network dysfunction; neural circuit; neural network; neuropathology; neuroregulation; novel; novel strategies; preservation; response; risk variant; single-cell RNA sequencing; tau Proteins; transcription factor REST; transcriptome; transcriptome sequencing

This RO1 grant proposal is in response to FOA: PAR-19-070, Notice NOT-AG-19-033 “Selective Cell and Network Vulnerability in Aging and Alzheimer's Disease”. Memory loss in Alzheimer's disease (AD) reflects a progressive failure of neural network function. The overall goal of this proposal is to explore a novel paradigm for the role of neural networks and the REST transcription factor in brain aging and AD. We have shown that REST is activated in the aging human brain but not in AD, where it fails beginning at the stage of mild cognitive impairment. Furthermore, we have recently demonstrated that regulation of neural network activity by REST is involved in a conserved mechanism of longevity and cognitive preservation. Our preliminary studies indicate that REST loss-of- function gives rise to cognitive decline, and markedly augments amyloid and tau pathology in several AD mouse models. It remains to be determined, however, whether REST selectively affects critical neural circuits or acts more globally. We have generated brain conditional floxed REST knockout mice, and now propose to generate REST knockout mice that selectively target entorhinal cortical neurons, CA1 or CA3 hippocampal neurons, or inhibitory GABAergic interneurons. These novel conditional REST knockout lines, together with two established AD transgenic lines, will be used to interrogate the role of REST in the entorhinal (EC)-hippocampal circuit that plays an essential role in memory formation and is central to the onset of AD. Specifically, selective effects of targeted REST deletion on neural network excitation, synaptic plasticity, memory, amyloid deposition and the propagation of tau pathology will be assessed. Our working hypothesis is that REST will play a central role in the regulation of EC-hippocampal network homeostasis, and that a breakdown of network function is an early component of AD. To complement these in vivo studies, we have established a cerebral organoid model of sporadic AD and APOE4 to interrogate neural network function. Cerebral organoids derived from sporadic AD and APOE4 gene-edited iPS cells will be examined for altered neural network activity and tau propagation, and the role of REST. Non-invasive electrical stimulation will be explored in cerebral organoids as an intervention for ameliorating network dysfunction. Finally, we will employ a powerful new platform for single cell RNA-seq and ATAC-seq in the brain. This approach will be applied to mouse models and the human brain to discover gene networks that protect against age- and AD-related memory loss. This multidisciplinary approach will involve collaborating investigators with expertise ranging from genomic biology to electrophysiology and neuropathology, in a coordinated effort to advance the understanding of selective neural network dysfunction in AD.

此 RO1 拨款提案是对 FOA 的回应：PAR-19-070，通知 NOT-AG-19-033“选择性细胞 以及衰老和阿尔茨海默病中的网络脆弱性”。阿尔茨海默病 (AD) 导致的记忆丧失 反映了神经网络功能的逐渐失效。该提案的总体目标是探索一种新颖的 神经网络和 REST 转录因子在大脑衰老和 AD 中的作用范例。我们有 研究表明，休息在衰老的人脑中被激活，但在 AD 中则不然，在 AD 阶段它就失效了。 轻度认知障碍。此外，我们最近证明了神经网络的调节 REST 活动涉及长寿和认知保存的保守机制。我们的 初步研究表明，休息功能丧失会导致认知能力下降，并显着加剧 几种 AD 小鼠模型中的淀粉样蛋白和 tau 蛋白病理学。然而，REST 是否有效仍有待确定 选择性地影响关键神经回路或更全局地发挥作用。我们已经生成了大脑条件 floxed REST 基因敲除小鼠，现在提议生成选择性靶向内嗅的 REST 基因敲除小鼠 皮质神经元、CA1 或 CA3 海马神经元或抑制性 GABA 能中间神经元。这些小说 条件性 REST 敲除系以及两个已建立的 AD 转基因系将用于询问 REST 在内嗅 (EC)-海马回路中的作用，该回路在记忆形成中发挥重要作用 并且是 AD 发病的核心。具体来说，目标 REST 删除对神经网络的选择性影响 兴奋、突触可塑性、记忆、淀粉样蛋白沉积和 tau 病理学的传播将 评估。我们的工作假设是 REST 将在 EC-海马的调节中发挥核心作用 网络稳态，网络功能崩溃是 AD 的早期组成部分。来补充 通过这些体内研究，我们建立了散发性 AD 和 APOE4 的脑类器官模型来探究 神经网络功能。源自散发性 AD 和 APOE4 基因编辑 iPS 细胞的大脑类器官将 检查神经网络活动和 tau 传播的改变，以及 REST 的作用。非侵入性 将在大脑类器官中探索电刺激作为改善网络的干预措施 功能障碍。最后，我们将采用一个强大的新平台进行单细胞 RNA-seq 和 ATAC-seq 脑。这种方法将应用于小鼠模型和人脑，以发现基因网络 防止与年龄和 AD 相关的记忆丧失。这种多学科方法将涉及合作 具有从基因组生物学到电生理学和神经病理学等专业知识的研究人员 协调努力以增进对 AD 选择性神经网络功能障碍的理解。