Major Histocompatibility Complex I regulation of microglial function in aging and Alzheimer's Disease

Abstract: Systemic and CNS sterile inflammation (inflammaging) are proposed drivers of brain aging and neurodegenerative diseases (e.g., Alzheimer’s disease, AD). Microglia, the resident CNS macrophages, alter their phenotype with aging and AD, but how this reactivity contributes to, or prevents, AD development and

progression is unclear. An overarching view in the field is that microgliosis initially protects against accumulating damage in the aged brain, but with time and AD neuropathology, persistent hyperactivation becomes deleterious and promotes neurodegeneration. In our studies, we have identified a relatively unexplored aspect of

neuroinflammation with aging and AD characterized by upregulation of the Major Histocompatibility Complex I (MHC-I). Microglial MHC-I is induced in humans, mice, and other species with aging, and occurs in AD patients and AD mouse models. We have also determined that antigen-independent MHC-I receptors, leukocyte

immunoglobulin-like receptor subfamily receptors (Lilr) and paired immunoglobulin-like type 2 receptors (Pilr), are also present and induced in microglia with aging and AD. These receptors are almost exclusively restricted to microglia in the CNS and contain either immunoreceptor tyrosine-based activation or inhibition motifs (pro-

inflammatory ITAMs and anti-inflammatory ITIMs, respectively) that regulate Syk activity, a central modulator of microglial phenotype. Thus, in the absence of, or in addition to, canonical signaling to T cell receptors on T cells, MHC-I could cell-autonomously regulate microglial phenotype through Lilrs/Pilrs and this Syk. We hypothesize

that MHC-I is a cell-autonomous regulatory mechanism for microglia that promotes a pro-inflammatory phenotype and alters microglia function. This proinflammatory microglial phenotype may also help recruit infiltrating T cells to the brain parenchyma here MHC-I could signal directly to T cells. 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, 2) Determine if MHC-I suppression exacerbates prodromal AD phenotypes while slowing progression after symptom onset, and 3) Determine if T cell infiltration

into the brain and phenotype with aging and in models of AD is dependent on microglial MHC-I. Validation of MHC-I as a novel regulator of microglial function will open new research avenues into controlling microglial function and regulating T cell infiltration and function.