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

项目摘要--项目2 脑老化和阿尔茨海默病(P3)围绝经期的使命是发现生物学 围绝经期过渡期间发生的脑内变化导致内表型预测 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，我们把重点放在神经免疫系统作为一个关键 中年女性大脑发生的时序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病的风险表型。项目2通过以下方式帮助实现P3目标 确定在中年时间和内分泌老化过程中被激活的免疫生物学系统， 免疫转录组和表型、贡献细胞、神经图谱的动态转换 特定针对免疫转换每个阶段的免疫反应和治疗方法。整体而言 指导项目2研究计划的假设是，免疫系统是 大脑中的代谢危机。根据我们的初步证据，我们推测大脑中的神经免疫模式 会动态地与内分泌衰老阶段相关。此外，我们假设APOE基因将是一种 大脑中生物神经免疫系统的关键调节器。目标1解决基础系统生物学问题 大脑中生物能量系统和免疫系统之间的接口。目标1的分析将确定动态 神经免疫的基因/表型特征在前期、围产期和 绝经后过渡。目标2的目标是为精确的免疫调节奠定基础。 基于内分泌老化状态和载脂蛋白E的降低女性阿尔茨海默病风险的治疗 这将通过计算医学生物信息学策略来实现。翻译目标 目标3是创建一个基于APOE4遗传负担和精确神经免疫治疗的平台 内分泌老化状况。目标3将通过以下方式实现：1)整合神经免疫信号 来自Aim 1和Aim 2的治疗候选；2)用神经免疫治疗特异性治疗hAPOE小鼠 内分泌衰老过渡；3)精确神经免疫疗法预防、延缓和 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一个 在这个平台上实现精确的神经免疫医学干预，正确的治疗在正确的地方 在正确的APOE基因中的时间。 这里提出的研究解决了美国国家老龄问题研究所2016年的战略目标： 21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 第一天、第二天和第四天。

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.