Characterization and regulation of the major histocompatibility complex class I in the Cns: functional implications for brain aging and sexually dimorphic differences in neuroinflammation
Open Access
- Author:
- Vankirk, Colleen Amanda
- Graduate Program:
- Pharmacology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 17, 2013
- Committee Members:
- Dr Willard M Freeman, Dissertation Advisor/Co-Advisor
Kent Eugene Vrana, Committee Member
Andras Hajnal, Committee Member
Scot R Kimball, Committee Member
Melvin Lee Billingsley, Committee Member - Keywords:
- aging
MHCI
brain
neuroinflammation - Abstract:
- Cognitive impairments with non-neurodegenerative brain aging are associated with synapse loss and diminished synaptic plasticity. The molecular mechanisms underlying synaptic loss and reduced plasticity with normal brain aging are unknown and identification of these pathways could provide targets for therapeutics to either prevent cognitive decline or slow its progression. The major histocompatibility complex class I (MHCI) processing and presentation pathway was first described in the immune system and serves to detect viral antigens and destroy infected cells. However, it has recently been discovered that MHCI is functionally pleiotropic, and plays important roles in the CNS including participating in activity-dependent structural remodeling processes, synaptic refinement, and synaptic plasticity. Previously, we have demonstrated a significant increase in MHCI processing and presentation pathway transcript expression in hippocampal synapses of aged male rats. Given that MHCI reduces glutamatergic and GABAergic synapse density, and under certain conditions, inhibits synaptic plasticity, aberrant MHCI regulation may be a mechanistic pathway in brain aging. With the recent discovery of these new functions of MHCI in the CNS, there is a paucity of data on the expression, localization, and regulation of the MHCI pathway in the CNS across the lifespan in both males and females. This information is required in order to understand MHCI function in the CNS. These studies sought to 1) characterize regional and cellular expression of MHCI across the CNS, 2) examine DNA promoter methylation as a regulatory mechanism underlying differences in MHCI expression across neural regions, 3) assess DNA promoter methylation as a regulatory mechanism underlying differences in MHCI gene expression across ages and sex, 4) determine changes in MHCI and inflammatory transcript expression with advanced age in both males and females across neural regions, and 5) test acute changes in sex hormones as a potential regulatory mechanism controlling MHCI and inflammatory gene expression. We found that MHCI expression is ubiquitously expressed across neural regions but quantitative expression patterns vary significantly. These differences in expression may be regulated through DNA promoter methylation as methylation levels of two classical MHCI isoforms, H2-D1 and H2-K1, differed between regions and were inversely correlated with expression levels. MHCI expression is apparent primarily in neurons across all areas of the CNS examined with some expression in microglia as well. Additionally, inductions in MHCI expression with advanced age were replicated in both male and female mice, with females demonstrating higher induction in inflammatory transcripts when compared to males, suggesting an influence by sex hormones in the regulation of MHCI and inflammatory factors. DNA promoter methylation does not appear to regulate MHCI transcript expression changes with age. When testing the hypothesis that sex hormones, specifically estrogen, control MHCI expression, we found that MHCI expression did not vary across the estrous cycle, however, inflammatory transcripts were significantly regulated across the cycle, with higher expression being evident in hypoestrogenic periods. The results of these studies demonstrate that differences in MHCI expression across CNS regions are likely regulated in part through gene promoter methylation. Age-related induction of MHCI and inflammatory gene expression occurs across the CNS in both males and females, with females demonstrating higher expression when compared to age-matched males, suggesting a potential sex-hormone component to regulation. However, MHCI expression does not appear to be regulated acutely by changes in circulating sex hormones in young females, but other inflammatory genes are. The latter results provide an important new avenue of research examining changes in local neuroinflammation that may affect cognitive processes with acute alterations in circulating sex hormones. These studies may also provide insight into age and/or sex related differences in stroke, learning and memory, Alzheimer’s disease, and CNS connectivity and plasticity given the expanding functional roles for MHCI in the CNS.