Targeting REST in Alzheimer's Disease

针对阿尔茨海默病的休息

• 批准号: 10396653
• 负责人: Bruce A YANKNER
• 金额: $ 90.13万
• 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/10396653
• 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; gene network; 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.

项目概要/摘要 阿尔茨海默病 (AD) 中的记忆丧失反映了神经网络功能的逐渐衰竭 病理学和神经炎症。该提案的总体目标是探索一种新的范式 REST 转录因子在 AD 神经网络和小胶质细胞功能调节中的作用 推进新的治疗方法。我们发现主要的发育调节器 REST/NRSF 是 在衰老的人脑中诱导并协调保护衰老的基因网络的表达 神经元免受神经毒性应激和过度兴奋。从 AD 阶段开始，REST 被下调 轻度认知障碍。我们对条件性 REST 缺陷小鼠的初步研究表明，REST 防止淀粉样蛋白和 tau 蛋白病理，以及 AD 小鼠模型的认知能力下降。开始 了解 REST 在关键神经回路中的作用，我们将在 第二层内嗅皮层神经元，或 CA1 或 CA3 海马神经元，内嗅神经元的组成部分 AD 早期受影响的皮质 (EC)-海马回路。这些新型 REST 基因敲除小鼠将进行杂交 使用已建立的 AD 转基因系来探索对神经网络兴奋、突触可塑性、 记忆和病理学。我们还将扩展最近的初步研究，表明 REST 在小胶质细胞中丢失 AD，并且 REST 缺陷的小胶质细胞功能受损。为了探索 REST 在小胶质细胞中的作用，我们 已经生成了条件性小胶质细胞 REST 敲除小鼠系。该小鼠模型以及初级 小胶质细胞培养物将用于研究 REST 调节的免疫/炎症信号通路， 以及对吞噬作用和 Aβ 清除的影响。将进行 RNA-seq 和 ChIP-seq 分析 广泛定义影响小胶质细胞功能的 REST 调节基因网络和信号通路。一个中央 问题是 REST 是否是一个可药物靶标。我们已经发现了新型 REST 激活药物，可以预防 AD 小鼠模型的记忆丧失和病理学。 REST 缺陷小鼠的药物活性丧失，表明 REST 的特异性。重要的是，原型 REST 激活药物没有显示出毒性证据 长期给药两年以上的小鼠。这些新颖的代理不仅提供了证据 翻译原则，但也是发现 REST 介导的潜在机制的宝贵工具 神经保护。其中一种机制是未折叠蛋白反应，它可能受到 REST 的调节 通过将要研究的目标基因和信号通路进行激活。这个多学科 该方法可能为衰老和 AD 的神经保护机制提供新的见解，并有可能 重要的治疗意义。