Targeting REST in Alzheimer's Disease

针对阿尔茨海默病的休息

• 批准号: 10209714
• 负责人: Bruce A YANKNER
• 金额: $ 91.67万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209714
• 关键词: Abeta clearance; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Brain; Cell Culture Techniques; ChIP-seq; Chronic; Development; Failure; Functional disorder; Genes; Goals; Hippocampus (Brain); Human; Immune; Impaired cognition; Inflammatory; Intervention; Knock-out; Knockout Mice; Longevity; Mediating; Memory; Memory Loss; Microglia; Mus; Neurons; Pathology; Peripheral; Phagocytosis; Pharmaceutical Preparations; Proteins; Regulation; Role; Signal Pathway; Site; Specificity; Stress; Synaptic plasticity; Therapeutic; Toxic effect; Transgenic Organisms; Translations; aging brain; druggable target; entorhinal cortex; functional disability; improved; insight; interdisciplinary approach; knockout gene; mild cognitive impairment; mouse model; neural circuit; neural network; neuroinflammation; neuron component; neuroprotection; neurotoxic; novel; novel therapeutic intervention; prevent; prototype; response; tau Proteins; tool; transcription factor REST; transcriptome sequencing

Project Summary/ Abstract Memory loss in Alzheimer's disease (AD) reflects a progressive failure of neural network function in the setting of pathology and neuroinflammation. The overall goal of this proposal is to explore a novel paradigm for the role of the REST transcription factor in the modulation of neural networks and microglial function in AD, and to advance a new therapeutic approach. We discovered that the master developmental regulator REST/NRSF is induced in the aging human brain and coordinates the expression of a gene network that protects aging neurons from neurotoxic stress and hyperexcitation. REST is downregulated in AD, beginning at the stage of mild cognitive impairment. Our preliminary studies in conditional REST-deficient mice indicate that REST protects against amyloid and tau pathology, as well as cognitive decline in AD mouse models. To begin to understand the role of REST in critical neural circuits, we will generate highly selective knockouts of REST in layer II entorhinal cortical neurons, or in CA1 or CA3 hippocampal neurons, components of the entorhinal cortex (EC)-hippocampal circuit that is affected early in AD. These novel REST knockout mice will be crossed with established AD transgenic lines to explore effects on neural network excitation, synaptic plasticity, memory and pathology. We will also extend recent preliminary studies showing that REST is lost in microglia in AD, and that REST-deficient microglia are functionally impaired. To explore the role of REST in microglia, we have generated a conditional microglial REST-knockout mouse line. This mouse model, together with primary microglial cell cultures, will be used to investigate REST-regulated immune/inflammatory signaling pathways, as well as effects on phagocytosis and Aβ clearance. RNA-seq and ChIP-seq analysis will be performed to broadly define REST-regulated gene networks and signaling pathways that affect microglial function. A central question is whether REST is a druggable target. We have identified novel REST-activating drugs that prevent memory loss and pathology in AD mouse models. Drug activity is lost in REST-deficient mice, indicating specificity for REST. Importantly, the prototype REST-activating drug does not show evidence of toxicity in mice following chronic administration for more than two years. These novel agents not only provide proof-of- principle for translation, but are also valuable tools for discovering underlying mechanisms of REST-mediated neuroprotection. One such mechanism is the unfolded protein response, which may be modulated by REST activation through target genes and signaling pathways that will be investigated. This multidisciplinary approach may provide novel insights into neuroprotective mechanisms in aging and AD, with potentially important therapeutic implications.

项目摘要/摘要 阿尔茨海默氏病（AD）中的记忆力丧失反映了环境中神经网络功能的进行性失败 病理和神经炎症。该提议的总体目标是探索一个新颖的范式 剩余转录因子在AD中的神经网络和小胶质功能的调制中的作用， 推进一种新的理论方法。我们发现总体开发调节器REST/NRSF是 在衰老的人脑诱导并协调保护衰老的基因网络的表达 神经毒性应激和过度刺激的神经元。休息在广告中被下调，从阶段开始 轻度认知障碍。我们在条件休息缺陷小鼠方面的初步研究表明静止 预防淀粉样蛋白和TAU病理学，以及AD小鼠模型的认知下降。开始 了解休息在关键神经回路中的作用，我们将产生高度选择性的静止敲除 第二层内hin骨皮质神经元，或在CA1或CA3海马神经元中（内嗅的成分） 在AD早期受影响的皮层（EC） - 海马电路。这些新颖的休息淘汰小鼠将被交叉 具有已建立的AD转基因线，以探索对神经网络兴奋，突触可塑性的影响， 记忆和病理。我们还将扩展最新的初步研究，表明在小胶质细胞中静止 AD，静止缺陷的小胶质细胞在功能上受损。探索休息在小胶质细胞中的作用，我们 已经生成了有条件的小胶质静止鼠标线。该鼠标模型，主要 小胶质细胞培养物将用于研究静止调节的免疫/炎症信号通路， 以及对吞噬作用和Aβ清除率的影响。 RNA-seq和CHIP-seq分析将进行 广泛定义的静止调节基因网络和影响小胶质功能的信号通路。中央 问题是休息是否是可吸毒的目标。我们已经确定了新型的休息激活药物，以防止 AD鼠标模型中的记忆丧失和病理。药物活性在缺陷的小鼠中丢失，表明 休息的特异性。重要的是，原型静止激活药物没有显示出毒性的证据 长期给药后两年以上的小鼠。这些新颖的代理不仅提供了证明 翻译原则，但也是发现静止介导的基本机制的宝贵工具 神经保护。一种这样的机制是展开的蛋白质反应，可以通过静止调节 通过目标基因和信号通路的激活。这个多学科 方法可能会提供对衰老和AD中神经保护机制的新见解，并有可能 重要的治疗隐含物。