Targeting REST in Alzheimer's Disease

项目概要/摘要 阿尔茨海默病（AD）的记忆丧失反映了神经网络功能在环境中的进行性失效 病理学和神经炎症。该提案的总体目标是探索一种新的模式， 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， 提出一种新的治疗方法。我们发现主要的发育调节因子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 神经毒性应激和过度兴奋。REST在AD中下调，开始于 轻度认知障碍我们在条件性REST缺陷小鼠中的初步研究表明，REST 在AD小鼠模型中保护免受淀粉样蛋白和tau病理以及认知下降。开始 了解REST在关键神经回路中的作用，我们将在 第二层内嗅皮质神经元，或在CA 1或CA 3海马神经元，内嗅的成分 皮质（EC）-海马回路，在AD早期受到影响。这些新的REST敲除小鼠将被杂交， 用已建立的AD转基因株系研究对神经网络兴奋，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 已经产生了一个条件性小胶质细胞REST敲除小鼠系。这种小鼠模型，连同主要的 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REST调节的基因网络和影响小胶质细胞功能的信号通路。中央 问题是REST是否是一个可药物化的目标。我们已经确定了新的REST激活药物， AD小鼠模型中的记忆丧失和病理学。在REST缺陷小鼠中药物活性丧失，表明 REST的特性。重要的是，原型REST激活药物没有显示出毒性的证据， 长期给药超过两年的小鼠。这些新的代理商不仅提供证据- 翻译的基本原则，但也是发现REST介导的潜在机制的有价值的工具。 神经保护其中一种机制是未折叠蛋白质反应，它可能受到REST的调节 将研究通过靶基因和信号通路的激活。这种多学科 这种方法可能为衰老和AD的神经保护机制提供新的见解， 重要的治疗意义。

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.