Neurobiology of Aging

Microglial Signaling 

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.

Cell surface microglial MHC-I protein expression increases with aging. A In young (5–7 m.o.) mice (n = 6) CD11b⁺/CD45^mid hippocampal singlets were > 95% positive for panH2 staining, while the negative gate only ~ 5% of cells were positive. One-way ANOVA with SNK post hoc comparisons (***p < 0.001). B In young (5 m.o.) and old (24 m.o.) males and females, panH2 cell surface staining intensity was greater in hippocampal CD11b⁺/CD45^mid singlets compared to the negative gate and was more intense in old compared young. T-test,*p < 0.05, n = 4/age. C This finding was recapitulated with a second panH2 antibody. D Male and female, young (5 m.o) and old (24 m.o.) Cx3cr1.^Jung NuTRAP mouse hippocampal singlets were gated for EGFP and then assessed for panH2 staining intensity. Staining intensity was greater in old compared to young mice (t-test, *p < 0.05

From: Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans. Kellogg CM, Pham K, Machalinski  AH, Porter  HL , Blankenship HE, Tooley KB, Stout  MB, Rice HC, Sharpe AL, Beckstead ML, Chucair-Elliott AJ, Ocañas SR, Freeman WM. Geroscience. 2023 Oct;45(5):3019-3043.