Regulation of Microglial Function by Major Histocompatibility Complex I in Aging and Alzheimer's Disease - Abstract Understanding the pathological changes that occur with aging and lead to loss of cellular or organ function has implications for a wide range of age-related diseases. As other diseases and disorders are cured and treated, life expectancy increases, and the need to increase the ‘healthspan’ is becoming more important. There is a sterile increase in inflammation with age, known as ‘inflammaging’. This is true with brain aging and is centered around microglia, the resident myeloid cells of the brain. Our overarching hypothesis is that microgliosis initially protects against accumulating damage in the aged brain, but with time and Alzheimer’s disease (AD) neuropathology, persistent hyperactivation becomes deleterious and promotes neurodegeneration. Recently, our lab has discovered a consistent microglial induction of Major Histocompatibility Complex I (MHC-I) pathway genes and corresponding receptors (leukocyte immunoglobulin-like receptor subfamily receptors [LILRs] and paired immunoglobulin-like type 2 receptors [PILRs]) with age and in Alzheimer’s. These receptors are almost exclusively restricted to microglia in the CNS and could regulate microglial reactivation. Previously, the brain was thought of as ‘immune privileged’; however, in recent years, it has been discovered that these immune genes are expressed in the brain, and they often have pleiotropic functions. MHC-I classically presents intracellular antigens to immune cells to mount an immune response; however, their role in brain aging is thus far unknown. Microglia become more reactive with age and change to more pro-inflammatory phenotypes. Our hypothesis is that the increased expression of MHC-I and their receptors is a mechanism through which microglia can signal cell-autonomously to themselves or cell-non-autonomously to other microglia to induce phenotypic switching to a more reactive phenotype. Whether this is a protective measure or harmful during aging is unknown, and our mouse model to block MHC-I function specifically in microglia will allow us to elucidate for the first time whether this change with aging is beneficial or harmful, and this can provide an avenue for future therapies. Additionally, this same trend of increasing MHC-I expression with aging has been observed in microglia in various AD mouse models and human AD cases. As such, we are also investigating the role of MHC-I in the case of AD by crossing our MHC-I knockout mouse with an AD mouse line to determine the role of this gene in the pathogenesis of AD. Elucidating the role of these genes in the pathogenesis of AD onset and progression will provide novel insight into the role of microglia in AD. Using a novel, temporally controlled and microglia-specific MHC-I knockout model we will: 1) Determine if MHC-I expression regulates microglial reactivity and phagocytic phenotypes with aging, and 2) Determine if MHC-I suppression exacerbates AD phenotypes prodromally while slowing progression after symptom onset.
