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

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.