Targeting a Novel Regulator of Brain Aging and Alzheimer's Disease

描述（由申请人提供）：本R01拨款申请是对RFA-AG-13-013“阿尔茨海默病新治疗靶点的跨学科鉴定和验证方法”的回应。大脑老化是老年人认知能力下降的原因之一，也是阿尔茨海默病（AD）的主要危险因素。尽管大脑在疾病中起着核心作用，但人们对大脑衰老的分子基础以及从正常到病理性衰老的转变知之甚少。本提案的总体目标是通过探索新发现的神经保护调节网络的作用，获得健康大脑衰老和向AD过渡的新见解。我们最近发现，主要的发育调节因子REST/NRSF在衰老的人脑中被诱导，并与HDAC1一起协调一个基因网络的表达，该基因网络可能保护衰老的神经元免受神经毒性应激、突触丢失和过度兴奋的影响。这一途径调控了衰老大脑中涉及细胞死亡、炎症、氧化应激和AD病理的大量基因的表达。REST的诱导与衰老过程中认知功能的保存相关，而在轻度认知障碍患者中，功能丧失与认知能力下降的发生有关。REST功能在AD患者的受影响脑区几乎完全被废除。我们的初步结果暗示这一途径在调节两种主要的细胞类型在老化的大脑，神经元和小胶质细胞。本研究旨在通过REST和HDAC1条件敲除小鼠，阐明REST网络在保护衰老神经元免受年龄相关应激源、减少神经炎症和保持认知功能方面的调节作用。新的高灵敏度转录组测序技术以及使用个人基因组计划工具的信息学分析将用于定义rest调控的基因网络。通过将这种系统遗传学方法应用于宗教秩序研究中具有良好特征的人脑样本，我们将尝试定义rest调节的基因网络，预测成功衰老，早期认知能力下降和AD。一个核心问题是，这种基因网络是如何在阿尔茨海默病个体中系统性地失效的，以及这种衰退是否可以逆转。REST可以通过使用已知药物以及新发现的小分子药物刺激Wnt信号来激活，这一发现提出了一种令人兴奋的可能性，即基于REST网络激活的新型治疗方法可以保护老化的大脑。这些研究将汇集三位主要研究者和许多合作者，他们具有不同但互补的专业领域，以多学科方法了解从正常大脑衰老到阿尔茨海默病的转变。

DESCRIPTION (provided by applicant): This R01 grant proposal is in response to RFA-AG-13-013 "Interdisciplinary Approach to Identification and Validation of Novel Therapeutic Targets for Alzheimer's Disease". The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease (AD). Despite this central role in disease, the molecular underpinnings of brain aging and the transition from normal to pathological aging are poorly understood. The overall goal of this proposal is to gain new insights into healthy brain aging and the transition to AD by exploring the role of a newly identified neuroprotective regulatory network. We have recently discovered that the master developmental regulator REST/NRSF is induced in the aging human brain and together with HDAC1 coordinates the expression of a gene network that may protect aging neurons from neurotoxic stress, synapse loss and overexcitation. This pathway regulates the expression of a large number of genes in the aging brain that are involved in cell death, inflammation, oxidative stress and AD pathology. Induction of REST correlates with preservation of cognitive function during aging, whereas loss of function is associated with onset of cognitive decline in patients with mild cognitive impairment. REST function is almost completely abrogated in affected brain regions in AD. Our preliminary results implicate this pathway in the regulation of two major cell types in the aging brain, neurons and microglia. The studies in this proposal seek to elucidate the regulatory role of the REST network in protecting aging neurons from age-related stressors, reducing neuroinflammation and preserving cognitive function using REST and HDAC1 conditional knockout mice. New high-sensitivity transcriptome sequencing technology together with informatics analysis using tools from the Personal Genome Project will be used to define the REST-regulated gene network. By applying this systems genetics approach to well-characterized human brain samples from the Religious Orders study, we will attempt to define REST-regulated gene networks predictive of successful aging, early cognitive decline and AD. A central question is how this gene network systematically fails in individuals who develop AD, and whether this decline can be reversed. The discovery that REST can be activated through stimulation of Wnt signaling using known drugs, as well as newly identified small molecule agents, raises the exciting possibility that the aging brain could be protected by a novel therapeutic approach based on activation of the REST network. These studies will bring together three principal investigators and many collaborators with diverse but complementary areas of expertise in a multidisciplinary approach to understand the transition from normal brain aging to AD.