Project 2: Metabolic and Immune Systems of Biology Interactions as Initiators and Drivers of Alzheimer's Pathology in Brain: Therapeutic Targets and Windows

项目概要-项目2 围绝经期脑老化和阿尔茨海默病（P3）的使命是发现生物学 在围绝经期过渡期间发生的大脑中的转变，导致内表型预测 阿尔茨海默病（AD）的风险。每年约有150万美国妇女进入围绝经期， 女性特有的神经内分泌过渡状态。在这里，我们专注于神经免疫系统作为一个关键， 中年女性大脑中发生的时间和内分泌老化的驱动因素。我们的目标是找出 这些转变发生的机制，并将这些发现转化为战略， 防止转化为阿尔茨海默氏症风险表型。项目2通过以下方式帮助实现项目3目标： 确定免疫生物学系统在中年时间和内分泌衰老中激活， 免疫转录组和表型的动态转换，贡献细胞，神经细胞图， 免疫应答和特异性靶向免疫转化每个阶段的治疗剂。整体 指导项目2研究计划的假设是，免疫系统是免疫系统的启动者和驱动者。 大脑代谢危机基于我们的初步证据，我们预期大脑中的神经免疫状况 将取决于动态和内分泌衰老阶段。此外，我们假设APOE基因型将是一个 大脑中生物学神经免疫系统的关键调节器。目标1涉及基础系统生物学， 大脑中生物能量和免疫系统之间的接口。目标1分析将确定动态 神经免疫基因型/表型签名，出现在过程中的前，后， 绝经后过渡期。目标二是为精确的免疫调节奠定基础 基于内分泌衰老状态和载脂蛋白E降低女性阿尔茨海默病风险的疗法 基因型，这将通过计算医学生物信息学策略实现。翻译目标 目标3是建立一个基于APOE 4遗传负荷的精确神经免疫治疗平台， 内分泌衰老状态目标3的目标将通过以下方式实现：1）整合来自神经免疫签名， 2）用来自目标2的治疗候选物治疗hAPOE小鼠; 向内分泌衰老过渡; 3）确定精确神经免疫治疗的功效，以预防、延迟和 治疗阿尔茨海默病的标志性病理。总的来说，这些分析的结果将提供 平台上，实现精准神经免疫医学干预与正确的治疗在正确的 时间在正确的APOE基因型。 本文提出的研究解决了国家老龄化研究所2016年的战略目标： 世纪：老龄化研究的战略方向，特别是目标A1、2、3、7、8和11以及目标 D1、2和4。

PROJECT SUMMARY – PROJECT 2 The mission of the Perimenopause in Brain Aging and Alzheimer’s disease (P3) is to discover biological transformations in brain that occur during the perimenopausal transition that lead to endophenotypes predictive of risk for Alzheimer’s disease (AD). Each year ~1.5 million American women enter into the perimenopause, a neuroendocrine transition state unique to the female. Herein, we focus on the neuro-immune system as a key driver of chronological and endocrinological aging that occurs in the midlife female brain. Our goals are to identify the mechanisms by which these transformations occur and to translate these discoveries into strategies to prevent conversion to an at-Alzheimer's-risk phenotype. Project 2 contributes to achieving P3 goals by determining the systems of immune biology activated across midlife chronological and endocrinological aging, the dynamic conversions in immune transcriptome and phenotype, the contributing cells, the map of neural immune responses and therapeutics that specifically target each stage of immune conversion. The overall hypothesis guiding Project 2 program of research is that the immune system is the initiator and driver of the metabolic crisis in brain. Based on our preliminary evidence, we anticipate that the neuro-immune profile in brain will be dynamic and endocrine aging stage dependent. Further, we hypothesize that APOE genotype will be a key regulator of the neuro-immune system of biology in brain. Aim 1 addresses fundamental systems biology of the interface between the bioenergetic and immune systems in brain. Aim 1 analyses will determine the dynamic neuro-immune genotypic/phenotypic signatures that emerge over the course of the pre, peri, and postmenopausal transition. The goal of Aim 2 is to establish a foundation for precision immune modulating therapies for reduction of Alzheimer’s disease risk in women based on endocrine aging status and APOE genotype which will be achieved through computational medical bioinformatics strategies. The translational goal of Aim 3 is to create a platform for precision neuro-immune therapy based on APOE4 genetic burden and endocrine aging status. Aim 3 objectives will be achieved by: 1) integrating neuro-immune signatures derived from Aim 1 with therapeutic candidates from Aim 2; 2) treating hAPOE mice with neuro-immune therapy specific to endocrine aging transition; 3) determining efficacy of precision neuro-immune therapy to prevent, delay and treat hallmark pathologies of Alzheimer’s disease. Collectively, outcomes of these analyses will provide a platform on which to achieve precision neuro-immune medicine to intervene with the right therapy at the right time in the right APOE genotype. Research proposed herein addresses strategic goals of the National Institutes on Aging’s 2016: Aging Well in the 21st Century: Strategic Directions for Research on Aging, specifically Goals A1, 2, 3, 7, 8 & 11 and Goals D1, 2, & 4.