title: CNS-wide Sexually Dimorphic Induction of the Major Histocompatibility Complex 1 Pathway With Aging.
abstract: 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, β2M, Lilrb3, Klra2, CD247) display markedly different expression profiles across the hippocampus, cortex, cerebellum, brainstem, and retina. MHCI components, receptors, associated inflammatory transcripts (IL1α, IL1β, IL6, TNFα), 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.
authors.affiliation: Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Mangold
authors.affiliation: Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey.|Department of Physiology, University of Oklahoma Health Sciences Center.|Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Dustin R
authors.initials: DR
authors.lastname: Masser
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center.|Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: David R
authors.initials: DR
authors.lastname: Stanford
authors.affiliation: Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Bixler
authors.affiliation: MD/PhD Program, College of Medicine, Pennsylvania State University, Hershey.
authors.forename: Aditya
authors.initials: A
authors.lastname: Pisupati
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation.
authors.forename: Cory B
authors.initials: CB
authors.lastname: Giles
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ford
authors.affiliation: Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.affiliation: Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey. wfreeman@ouhsc.edu.|Department of Physiology, University of Oklahoma Health Sciences Center.|Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center.
authors.forename: Willard M
authors.initials: WM
authors.lastname: Freeman
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D008285:Major Histocompatibility Complex / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology
keywords: Aging; DNA methylation; Gene expression; MHCI; Sex differences; brain