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

> **NIH NIH RF1** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $2,027,220

## Abstract

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.

## Key facts

- **NIH application ID:** 10985578
- **Project number:** 1RF1AG085573-01A1
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** WILLARD M FREEMAN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,027,220
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985578

## Citation

> US National Institutes of Health, RePORTER application 10985578, Major Histocompatibility Complex I regulation of microglial function in aging and Alzheimer's Disease (1RF1AG085573-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10985578. Licensed CC0.

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