Neuroglial Expression of the MHCI Pathway and PirB Receptor Is Upregulated in the Hippocampus with Advanced Aging

Abstract

The hippocampus undergoes changes with aging that impact neuronal function, such as synapse loss and altered neurotransmitter release. Nearly half of the aged population also develops deficits in spatial learning and memory. To identify age-related hippocampal changes that may contribute to cognitive decline, transcriptomic analysis of synaptosome preparations from adult (12 months) and aged (28 months) Fischer 344-Brown Norway rats assessed for spatial learning and memory was performed. Bioinformatic analysis identified the MHCI pathway as significantly upregulated with aging. Age-related increases in mRNAs encoding the MHCI genes RT1-A1, RT1-A2, and RT1-A3 was confirmed by qPCR in synaptosomes and in CA1 and CA3 dissections. Elevated levels of the MHCI cofactor (B2m), antigen-loading components (Tap1, Tap2, Tapbp), and two known MHCI receptors (PirB, Klra2) were also confirmed. Protein expression of MHCI was elevated with aging in synaptosomes, CA1, and DG, while PirB protein expression was induced in both CA1 and DG. MHCI expression was localized to microglia and neuronal excitatory postsynaptic densities, and PirB localized to neuronal somata, axons and dendrites. Induction of the MHCI antigen processing and presentation pathway in hippocampal neurons and glia may contribute to age-related hippocampal dysfunction by increasing neuroimmune signaling or altering synaptic homeostasis.

Beta-2 microglobulin is important for disease progression in a murine model for amyotrophic lateral sclerosis

“…This receptor is located on axons, dendrites and neuronal somata (VanGuilder Starkey et al, 2012) and could thus easily facilitate plasticity. Additionally, β 2 m is localized at synapses and in synaptosomes (Shatz, 2009).…”

Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging

“…Pairwise post hoc analysis (Student–Newman–Keuls, p  < 0.05) was performed on those genes with a significant effect ( p  < 0.05) of age, sex, or interaction effect. Rather than a global multiple testing correction, genes passing the ANOVA and post hoc statistical criteria were filtered for only those with an absolute value fold-change cutoff of |1.2| in accordance with standards for microarray analysis [34] and as previously described [26, 31, 35]. These two rounds of statistical thresholds and fold-change cutoffs were used to produce gene lists with a balance of minimizing type I and type II errors rather than a blanket false discovery rate correction which can produce a high type II error rate [36].…”

Expression of NgR1-Antagonizing Proteins Decreases with Aging and Cognitive Decline in Rat Hippocampus

“…Behavioral stratification of subjects and dissection of CA1, CA3 and DG subregions has been described in detail elsewhere (VanGuilder et al, 2011a, 2012; VanGuilder Starkey et al, 2012, 2013.) All animal experiments were performed in accordance with IACUC and AALAC approved procedures. Briefly, mature adult (12 months) and aged (26 months) male Fischer 344 × Brown Norway (F1) hybrid rats were purchased from the National Institute on Aging rodent colony maintained by Harlan Industries (Indianapolis, IN) and housed singly in the OUHSC Reynolds Oklahoma Center on Aging barrier facility, with water and food (Purina Mills, Richmond, IN) freely available.…”