Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Abstract

Major Histocompatibility Complex I (MHC-I) function in the CNS is still being determined after previously being thought to be absent from the brain. MHC-I expression increases with brain aging in mouse, rat, and human whole tissue analyses. Neuronal MHC-I expression has been proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). However, the CNS cellular localization of MHC-I expression has been unclear. Across newly generated and publicly available ribosomal profiling, cell sorting, and single cell data, microglia were found to be the primary source of classical and non-classical MHC-I in mice and humans. TRAP-qPCR analysis of 3-6 m.o. and 18-22 m.o. mice revealed significant age-related induction of B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 in microglia but not in astrocytes and neurons. Across a timecourse from 12-23 m.o., microglial MHC-I gradually increases until 21 m.o. and then accelerates. MHC-I protein was also enriched in microglia and increased with aging. Expression of MHC-I binding Leukocyte Immunoglobulin-like (Lilr) and Paired immunoglobin-like type 2 (Pilr) receptors in microglia but not astrocytes or neurons opens the possibility of cell-autonomous signaling and are also increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in mouse AD models and human data across numerous studies and in RNA-Seq of microglia from APP-PSEN1 mice. MHC-I expression occurred concurrently with p16 suggesting an association with cellular senescence. The conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD open the possibility of cell-autonomous signaling to regulate microglial reactivation.

Glia-Mediated Antigen Presentation In The Retina During Degeneration

“…These data showed that resident immune cells upregulated MHC II and its pathway, suggesting their ability to present antigens to CD4 + helper T-cells. Supporting our results, similar interactions between MHC II + resident immune cells and CD4 + T-cells have been documented in other contexts, such as Tau-mediated neurodegeneration and aging in the murine brain (Askin & Wegmann, 2023; Kellogg et al, 2023; Zhang et al, 2022). In the retina, their interplay is well-characterized only in animal models of autoimmune uveitis (Lipski et al, 2017; Okunuki et al, 2019) and little is known in retinal degenerative diseases.…”

Microglial apolipoprotein E particles contribute to neuronal senescence and synaptotoxicity

“…Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these differentially expressed genes (DEGs) are enriched in pathways such as Epstein-Barr virus infection, cell cycle and cellular senescence ( Figures 3 B and S3 D). Specifically, genes associated with aging and senescence such as H2-K1, H2-D1/Q6/Q4/Q7, H2-T22/23, GADD45a, and Igftbp3, 44 were upregulated in neurons treated with microglial apoE particles ( Figure 3 C). Meanwhile, genes associated with cellular mitosis and cell cycle 44 , 45 were downregulated after microglial apoE particles treatment, including Ccnb1, Ccna2, Ccnb2, Ccne2, Cdk1, and foxm1 45 , 46 ( Figure 3 C).…”

“…Specifically, genes associated with aging and senescence such as H2-K1, H2-D1/Q6/Q4/Q7, H2-T22/23, GADD45a, and Igftbp3, 44 were upregulated in neurons treated with microglial apoE particles ( Figure 3 C). Meanwhile, genes associated with cellular mitosis and cell cycle 44 , 45 were downregulated after microglial apoE particles treatment, including Ccnb1, Ccna2, Ccnb2, Ccne2, Cdk1, and foxm1 45 , 46 ( Figure 3 C). Results from real-time (RT) PCR consistently validated differences in mRNA levels of these genes in neurons with different glial apoE particle treatments ( Figures 3 D and 3E).…”

Analysis of secreted small extracellular vesicles from activated human microglial cell lines reveals distinct pro‐ and anti‐inflammatory proteomic profiles

“…We next wanted to further explore the relative expression of the proteins in resting and LPS‐sEVs that related to the cell surface as this may provide insight into defining the microglia phenotype sEVs are derived from (Figure 5B). Interestingly, among the 19 proteins there were notable proteins involved in inflammation such as complement component C3, and major histocompatibility complex (MHC) Class I molecules [33] were significantly enriched on the surface of LPS‐sEVs. Of the 8 significant GO biological process terms, fibrinolysis (GO:0042730) was the most significantly enriched term (Figure 5C) with an enrichment for plasminogen activator inhibitor‐1 (PAI‐1) and plasminogen (PLMN) (Figure 5D), proteins commonly upregulated in AD [34].…”