Neuroinflammation plays a critical role in injury and degeneration in the central nervous system (CNS). Microglia (MG) are specialized resident myeloid cells in the CNS that play essential roles the innate immune response. MG also have essential roles in CNS development, plasticity and immune surveillance. CNS injury and neurodegeneration lead to inflammatory activation of MG. Activated MG perform dynamic functions that can be both supportive and destructive to neuronal health. In the adult CNS MG turnover occurs very slowly but new MG can be rapidly generated after depopulation or in response to injury. However the ontogeny of new MG in the adult CNS is still not fully understood. While MG progenitors (MGP) that colonize the developing brain are born in the embryonic yolk sac, recent reports suggest that MGP cells may also exist in the adult CNS. Thus MG plasticity may not only refer to the molecular and morphological changes of existing cells, but also the generation of new MG populations. Currently, little is known regarding the potential role of newly born microglia in Alzheimer's disease (AD). We are interested in understanding the regulation of MG behavior, including the generation and differentiation of newly born MG in the setting of neurodegeneration. We have developed novel methods to fate map and isolate a population of cells expressing both markers of progenitor state (prominin 1) and myeloid commitment (Cd45) from the adult mouse brain. This potential progenitor population is present in the uninjured adult CNS, can be isolated by fluorescence activated cell sorting (FACS) and will differentiate into mature MG in vitro and in vivo. The goals of this proposal are to 1) determine if AD pathology influences the proliferation, differentiation, and survival of newly born MG in the adult CNS, 2) to determine if MGP contribute to the microglia population associated with amyloid plaque, 3) examine whether AD pathology influences the epigenetic profile and transcriptome of adult MGP and 4) determine if the inflammatory activation pattern in MGP derived mature microglia is influenced by cellular age or origin. We will employ mouse models of AD that develop early amyloid plaque to determine if these pathological hallmarks of AD influence the population dynamics of the progenitor and mature MG populations. In addition, we plan to employ state of the art single cell sequencing approaches to study how AD pathology influences chromatin architecture and gene expression in these distinguishable populations of CNS myeloid cells. In summary, the accomplishment of these aims will help to further understand dynamics of MG populations and the influence of those population dynamics on the inflammatory response in AD brain.
Microglia are CNS inflammatory cells that contribute to the pathogenesis of a variety of neurological disorders. This proposal aims to study how Alzheimer disease (AD) influences a recently discovered population of cells that reside in adult CNS, express stem cell markers, proliferate in response to inflammatory signals and differentiate into mature microglia. We utilize a mouse model of AD and the newly discovered molecular markers of microglia progenitors to specifically isolate and study how these immature cells respond to AD pathology.
