Project 3: Peripheral Immune Activation on the Road to Development of Alzheimer's Disease: Therapeutic Targets and Windows

项目概要-项目3 美国每年约有150万妇女进入围绝经期，这是一种独特的神经内分泌过渡状态 对雌性来说在脑老化和阿尔茨海默病（P3）围绝经期的使命是发现 在围绝经期过渡期间发生的导致内表型的脑生物学转变 预测阿尔茨海默病（AD）的风险。在这里，我们专注于神经免疫系统作为一个关键的驱动程序， 中年女性大脑中发生的时间和内分泌老化。我们的目标是确定 这些转变发生的机制，并将这些发现转化为战略， 转化为阿尔茨海默氏症风险表型。项目3通过确定以下因素来帮助实现项目组合3的目标： 在中年时间和内分泌衰老的每个阶段， 有助于AD风险表型的发展，并确定AD的治疗干预措施 在自身免疫性疾病（AID）的背景下。观察表明增强的适应性细胞免疫 有助于AD中观察到的神经退行性变化，这些变化在治疗期间加剧。 脑膜周围转移指导项目3的总体假设是，中期外周炎症 生活中的内分泌变化有助于AD的发展和神经退行性变， 女性目的描述围绝经期过渡期出现的外周免疫表型， 评估自身免疫性发作和绝经之间的联系，并确定现有的治疗自身免疫性疾病的方法。 有效降低患AD风险的药物。目标2的目标是通过以下方式确定机制： 遗传危险因子APOE 4和HLA-DRB 1 *1501与AD和AID的发生发展有密切关系 表型在围绝经期过渡期。目标3的目的是确定 通过B细胞抗原呈递的免疫激活以使用神经变性。这一目标将通过以下方式实现： 评价小鼠模型免疫引起的免疫表型和神经退行性变化 来自Aim 2的淀粉样β蛋白或髓鞘少突胶质细胞糖蛋白。这些研究的结果将推动 我们对围绝经期全身性炎症在前驱症状中的作用的基本理解 AD的神经退行性变化，并确定治疗干预措施，以降低患有AD的女性的AD风险。 自身免疫性疾病（AID），他们已经处于发展认知功能障碍的较高风险中。 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： 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 D1、2和4。

PROJECT SUMMARY – PROJECT 3 Each year ~1.5 million American women enter into the perimenopause, a neuroendocrine transition state unique to the female. 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). 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 3 contributes to achieving P3 goals by determining peripheral immune signatures at each stage of midlife chronological and endocrinological aging, their contribution to the development of an at-risk-for AD phenotype, and identifying therapeutic interventions for AD in the context of autoimmune disease (AID). Observations suggest that augmented adaptive cellular immunity contributes to neurodegenerative changes seen in AD, that these changes are exacerbated during the perimenopausal transition. The overall hypothesis guiding Project 3 is that peripheral inflammation during mid- life endocrinological changes contributes to the development of AD and neurodegeneration later in the life of females. Aim characterizes peripheral immunophenotypes that emerge during the perimenopausal transition, evaluates the link between autoimmune flares and menopause, and identifies existing therapies for autoimmune disease that are effective at reducing the risk of developing AD. The goal of Aim 2 is to identify mechanisms by which the genetic risk factors APOE4 and HLA-DRB1*1501 contribute to development of AD and AID phenotypes during the perimenopausal transition. The objective of Aim 3 is to determine the contribution of immune activation by B-cell antigen presentation to neurodegeneration using. This objective will be achieved by evaluating immunophenotype and neurodegenerative changes resulting from immunization of mouse models from Aim 2 with amyloid beta or myelin oligodendrocyte glycoprotein. Outcomes of these studies will advance our fundamental understanding of the role of systemic inflammation during perimenopause in the prodromal neurodegenerative changes of AD and identify therapeutic interventions to reduce risk of AD in women with autoimmune disorders (AID) who are already at higher risk of developing cognitive dysfunction. 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.