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

项目摘要--项目3 每年约有150万美国妇女进入围绝经期，这是一种独特的神经内分泌过渡状态 献给雌性。脑老化和阿尔茨海默病(P3)围绝经期的任务是发现 在围绝经期过渡期间发生的导致内表型的脑内生物学变化 预测阿尔茨海默病(AD)的风险。在这里，我们将重点放在神经免疫系统作为关键驱动因素 发生在中年女性大脑中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防止 转化为阿尔茨海默病高危表型。项目3通过以下方式为实现P3目标做出贡献 在中年时间和内分泌衰老的每个阶段的外周免疫特征，其 对AD高危表型的发展和确定AD的治疗干预措施的贡献 在自身免疫疾病(AID)的背景下。观察表明，增强的适应性细胞免疫 导致阿尔茨海默病的神经退行性变化，这些变化在 围绝经期过渡。指导项目3的总体假设是中期的外周炎症 生活中的内分泌变化有助于AD的发展和晚年的神经变性 女性。目的描述围绝经期过渡期间出现的外周免疫表型， 评估自身免疫性疾病和更年期之间的联系，并确定现有的自身免疫疗法 能有效降低AD风险的疾病。目标2的目标是通过以下方式确定机制 遗传危险因子APOE4和HLA-DRB1*1501在AD和AID发病中的作用 围绝经期过渡期的表型。目标3的目标是确定以下方面的贡献 免疫激活由B细胞抗原提呈给神经退行性变使用。这一目标将通过以下方式实现 评价免疫小鼠模型引起的免疫表型和神经退行性改变 来自AIM 2的淀粉样β蛋白或髓鞘少突胶质细胞糖蛋白。这些研究的结果将会取得进展 我们对围绝经期全身性炎症在前驱症状中作用的基本认识 阿尔茨海默病患者的神经退行性改变及降低AD风险的治疗干预措施 自身免疫性疾病(AID)已经处于发展认知功能障碍的较高风险。 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 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.