Microglial subpopulations that contribute to resilience to Alzheimers disease

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is the most common form of dementia, with over 5 million individuals currently suffering from this neurodegenerative disorder. Despite the prevalence of AD, many individuals live into their 90s without any cognitive decline. A subset of these cognitively normal individuals have the amyloid-beta plaques and phosphorylated tau tangles associated with a pathological diagnosis of AD at post-mortem autopsy. These individuals are considered “resilient” to AD. One of the major physiological drivers of AD is neuroinflammation. Microglia, as the brain’s innate immune cells, are a central player in this neuroimmune process. Different microglial subpopulations drive different disease-responsive processes including beneficial or detrimental responses to pathology. My current work is identifying these microglial subpopulations in late- onset AD individuals. I hypothesize that the responses of specific microglial subpopulations to pathology may mediate the relationship between AD pathology and cognitive impairment. The goal of the proposed study is to 1) address key gaps in our understanding of microglial subpopulation responses in resilient individuals in both humans and mice, and 2) to develop the tools and model systems needed to manipulate specific microglial subpopulations. I will evaluate the microglial subpopulations present in both resilient humans and a mouse model of resilience to AD utilizing single-nucleus RNAseq datasets. I will also develop techniques to modify gene expression in specific microglial subpopulations which has not been done before and test them in both in vitro and in vivo model systems. This will enhance both our biological understanding of resilience to AD, and our technical ability to manipulate microglial subpopulations. The candidate is a Ph.D. neuroscientist with training in microglial biology, mouse models, behavioral neuroscience, and RNAseq analysis who maintains strong connections with those who perform the clinical and neuropathological diagnosis of AD. Dr. Prater is committed to scientific research related to understanding the biological mechanisms underlying the cognitive impairment associated with AD pathology and the mediators of the relationship between pathology and cognition. The proposal will capitalize on Dr. Prater’s expertise in microglial biology and specifically microglial subpopulations, behavioral neuroscience, and single- nucleus RNAseq analysis in individuals resilient to AD pathology while allowing her to develop skills in viral manipulation of microglial gene expression. The knowledge, data, and experience gained from this proposal will allow Dr. Prater to successfully compete for her first R01 focused on manipulating microglial subpopulations to enhance resilience to AD. Dr. Prater’s goal is to identify mediators of the relationship between AD pathology and cognitive impairment that can be modified to enhance resilience to AD, ultimately providing therapeutic potential for those patients.