CNS-wide sexually dimorphic induction of the major histocompatibility complex 1 pathway with aging

Colleen A. Mangold, Dustin R. Masser, David R. Stanford, Georgina V. Bixler, Aditya Pisupati, Cory B. Giles, Jonathan D. Wren, Matthew M. Ford, William E. Sonntag, Willard M. Freeman

    Research output: Contribution to journalArticlepeer-review

    49 Scopus citations


    The major histocompatibility complex I (MHCI) pathway, which canonically functions in innate immune viral antigen presentation and detection, is functionally pleiotropic in the central nervous system (CNS). Alternative roles include developmental synapse pruning, regulation of synaptic plasticity, and inhibition of neuronal insulin signaling; all processes altered during brain aging. Upregulation of MHCI components with aging has been reported; however, no systematic examination of MHCI cellular localization, expression, and regulation across CNS regions, life span, and sexes has been reported. In the mouse, MHCI is expressed by neurons and microglia, and MHCI components and receptors (H2-K1, H2-D1, ?2M, Lilrb3, Klra2, CD247) display markedly different expression profiles across the hippocampus, cortex, cerebellum, brainstem, and retina. MHCI components, receptors, associated inflammatory transcripts (IL1?, IL1?, IL6, TNF?), and TAP (transporter associated with antigen processing) components are induced with aging and to a greater degree in female than male mice across CNS regions. H2-K1 and H2-D1 expression is associated with differential CG and non-CG promoter methylation across CNS regions, ages, and between sexes, and concomitant increased expression of proinflammatory genes. Meta-analysis of human brain aging data also demonstrates age-related increases in MHCI. Induction of MHCI signaling could contribute to altered synapse regulation and impaired synaptic plasticity with aging.

    Original languageEnglish (US)
    Pages (from-to)16-29
    Number of pages14
    JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
    Issue number1
    StatePublished - Jan 2017


    • Aging
    • Brain
    • DNA methylation
    • Gene expression
    • MHCI
    • Sex differences

    ASJC Scopus subject areas

    • General Medicine


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