Cell-autonomous regulation of microglial reactivity with aging and Alzheimer's Disease

Background and Innovation: Microglia, the resident macrophages of the CNS, become reactive and change their phenotype with aging and Alzheimer’s Disease (AD). Whether this is a positively compensatory response or part of AD development and progression is unclear. A unifying hypothesis is that microglial reactivity initially serves to protect against accumulating damage with aging or in prodromal AD neuropathology but persistent hyperactivation causes damage on its own and promotes neurodegeneration. We have identified the Major Histocompatibility Complex I (MHC-I) as an unexplored aspect of neuroinflammation with aging and AD. MHC-I is upregulated in the microglial of humans, mice, and other species with aging, and in AD patients and AD mouse models. Canonically, MHC-I presents antigens to T cell receptors for recognition. Our findings also demonstrate that antigen-independent MHC-I receptors, leukocyte immunoglobulin-like receptor subfamily receptors (Lilr), and paired immunoglobulin-like type 2 receptors (Pilr), are 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. Recent findings also provide compelling evidence that microglia and microglial cytokines/chemokines serve to attract T cells into the brain parenchyma to alter AD progression. Thus, microglial MHC-I could both cell-autonomously regulate microglial phenotype as well as attracting T cells to signal to T cell receptors. We hypothesize that MHC-I is a cell-autonomous mechanism that promotes a pro-inflammatory microglial phenotype and alters microglia function as well as helping recruit and signal to infiltrating T-cells in the brain parenchyma. To test this hypothesis, we will temporally inhibit microglial MHC-I with aging and in amyloid and tau mouse models of AD. These studies will determine if MHC-I expression regulates microglial reactivity and phagocytic phenotypes with aging, is necessary for recruitment and modulates T cell phenotype with aging and in mouse AD models. By altering MHC-I function at different ages we will determine if MHC-I suppression exacerbates AD phenotypes prodromally while slowing progression after symptom onset. These studies will employ our novel mouse models, microglia isolation methods that avoid ex vivo confounds, and analytical techniques to explore a new aspect of microglial function regulation with aging and in AD models. Significance and Impact to Veterans Healthcare: Validation of MHC-I as a novel regulator of microglial function will open new research avenues into controlling microglial function to maintain brain health and treat neurodegenerative diseases common in Veterans. AD and other dementias are a central health issue for the veteran population with nearly half a million veterans diagnosed with AD. Veterans with dementia have more and longer hospitalizations. Past history of traumatic brain injury or post traumatic stress disorder increases risk for AD. Preventative treatments that slow onset of AD or that slow AD progression would have significant positive impacts on veteran health and reduce healthcare burden. Path to translation/implementation: Successful completion of these studies would confirm a role of microglial MHC-I in AD. Next steps would be to test pharmacological or cell therapy approaches to modulate MHC-I function in animal models that could be translated to humans. Project Number: 1I01BX006628-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: WILLARD FREEMAN | Institution: OKLAHOMA CITY VA MEDICAL CENTER, OKLAHOMA CITY, OK | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 NURD-E (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11054094