Role of Microglial Heterogeneity on Cognitive Resilience in Aging and Alzheimer’s Disease

PROJECT DESCRIPTION/ABSTRACT This NIH K08 proposal describes a five-year career development plan for Dr. Aivi T. Nguyen to obtain the necessary research and professional skills and serve as transition to become a successful, independently funded physician-scientist. Dr. Nguyen completed her clinical training in Anatomic Pathology and Neuropathology at the Hospital of the University of Pennsylvania, after which she pursued post-doctoral training under the mentorship of Dr. Edward B. Lee in the Translational Neuropathology Research Laboratory, University of Pennsylvania. Currently, Dr. Nguyen is an assistant professor at Mayo Clinic Rochester, MN and contributing neuropathologist to the Alzheimer’s Disease Research Center (ADRC) and Mayo Clinic Study of Aging (MCSA). Dr. Nguyen’s long-term research focus is examining the role of microglia in cognitive resilience, normal aging, and aging-related CNS diseases through integration of neuropathology and translational research approaches to better understand neuroinflammation in human disease. This K08 award will provide protected time to acquire expertise in integrating antemortem Alzheimer’s disease (AD) biomarkers and neuropsychiatric data with postmortem neuropathology and to obtain expertise in two-photon in vivo imaging of microglia in AD mouse models. Research will be performed under the mentorship of Dr. Prashanthi Vemuri, an expert in cognitive resilience and neuroimaging, and Dr. LongJun Wu, an expert in microglial dynamics and neuroimmune interactions using two photon in vivo imaging. This award will also provide protected time for Dr. Nguyen to gain expertise through formal coursework, scientific seminars, and scientific meetings. AD, neuropathologically defined by β-amyloid plaques and neurofibrillary tangles, progresses in a spatio- temporally distinct fashion that can be studied in vivo by recent advances in neuroimaging and fluid biomarkers. Several ante- and postmortem studies have shown a discrepancy between AD pathology extent and cognition, forming the basis of cognitive resilience. A potentially protective microglial subpopulation termed amyloid-responsive microglia (ARM) was previously described in a single-nuclei RNA sequencing study of human AD brain. Whether microglial heterogeneity, specifically ARM, contribute to resilience is unclear. This proposal leverages antemortem AD biomarkers, cognitive data, and postmortem tissue from MCSA participants to address these specific aims: (1) Determine postmortem ARM tissue expression association with antemortem fluid and neuroimaging biomarkers, and whether ARM may be predicted by biomarkers; (2) Evaluate differential ARM tissue expression in cognitively resilient individuals versus not, and test antemortem predictors; and (3) Examine ARM phagocytosis and effects on downstream neuronal dystrophy in the setting of AD genetic risk. These studies will drive the development of an independent research program to study microglial heterogeneity and its role in resilience and AD and provide better understanding of cognitive aging.