BackgroundAge-related cognitive dysfunction, including impairment of hippocampus-dependent spatial learning and memory, affects approximately half of the aged population. Induction of a variety of neuroinflammatory measures has been reported with brain aging but the relationship between neuroinflammation and cognitive decline with non-neurodegenerative, normative aging remains largely unexplored. This study sought to comprehensively investigate expression of the MHC II immune response pathway and glial activation in the hippocampus in the context of both aging and age-related cognitive decline.MethodsThree independent cohorts of adult (12-13 months) and aged (26-28 months) F344xBN rats were behaviorally characterized by Morris water maze testing. Expression of MHC II pathway-associated genes identified by transcriptomic analysis as upregulated with advanced aging was quantified by qPCR in synaptosomal fractions derived from whole hippocampus and in hippocampal subregion dissections (CA1, CA3, and DG). Activation of astrocytes and microglia was assessed by GFAP and Iba1 protein expression, and by immunohistochemical visualization of GFAP and both CD74 (Ox6) and Iba1.ResultsWe report a marked age-related induction of neuroinflammatory signaling transcripts (i.e., MHC II components, toll-like receptors, complement, and downstream signaling factors) throughout the hippocampus in all aged rats regardless of cognitive status. Astrocyte and microglial activation was evident in CA1, CA3 and DG of intact and impaired aged rat groups, in the absence of differences in total numbers of GFAP+ astrocytes or Iba1+ microglia. Both mild and moderate microglial activation was significantly increased in all three hippocampal subregions in aged cognitively intact and cognitively impaired rats compared to adults. Neither induction of MHCII pathway gene expression nor glial activation correlated to cognitive performance.ConclusionsThese data demonstrate a novel, coordinated age-related induction of the MHC II immune response pathway and glial activation in the hippocampus, indicating an allostatic shift toward a para-inflammatory phenotype with advancing age. Our findings demonstrate that age-related induction of these aspects of hippocampal neuroinflammation, while a potential contributing factor, is not sufficient by itself to elicit impairment of spatial learning and memory in models of normative aging. Future efforts are needed to understand how neuroinflammation may act synergistically with cognitive-decline specific alterations to cause cognitive impairment.
Age-related cognitive decline occurs without frank neurodegeneration and is the most common cause of memory impairment in aging individuals. With increasing longevity, cognitive deficits, especially in hippocampus-dependent memory processes, are increasing in prevalence. Nevertheless, the neurobiological basis of age-related cognitive decline remains unknown. While concerted efforts have led to the identification of neurobiological changes with aging, few age-related alterations have been definitively correlated to behavioral measures of cognitive decline. In this work, adult (12 Months) and aged (28 months) rats were categorized by Morris water maze performance as Adult cognitively Intact, Aged cognitively Intact or Aged cognitively Impaired, and protein expression was examined in hippocampal synaptosome preparations. Previously described differences in synaptic expression of neurotransmission-associated proteins (Dnm1, Hpca, Stx1, Syn1, Syn2, Syp, SNAP25, VAMP2 and 14-3-3 eta, gamma, and zeta) were confirmed between Adult and Aged rats, with no further dysregulation associated with cognitive impairment. Proteins related to synaptic structural stability (MAP2, drebrin, Nogo-A) and activity-dependent signaling (PSD-95, 14-3-3θ, CaMKIIα) were up- and down-regulated, respectively, with cognitive impairment but were not altered with increasing age. Localization of MAP2, PSD-95, and CaMKIIα demonstrated protein expression alterations throughout the hippocampus. The altered expression of activity- and structural stability-associated proteins suggests that impaired synaptic plasticity is a distinct phenomenon that occurs with age-related cognitive decline, and demonstrates that cognitive decline is not simply an exacerbation of the aging phenotype.
Purpose-Pro-inflammatory environments in the brain have been implicated in the onset and progression of neurological disorders. In the present study, we investigate the hypothesis that brain irradiation induces regionally specific alterations in cytokine gene and protein expression.Materials and methods-Four month old F344 × BN rats received either whole brain irradiation with a single dose of 10 Gy γ-rays or sham-irradiation, and were maintained for 4, 8, and 24 h following irradiation. The mRNA and protein expression levels of pro-inflammatory mediators were analysed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining. To elucidate the molecular mechanisms of irradiation-induced brain inflammation, effects of irradiation on the DNA-binding activity of pro-inflammatory transcription factors were also examined.Results-A significant and marked up-regulation of mRNA and protein expression of proinflammatory mediators, including tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1), was observed in hippocampal and cortical regions isolated from irradiated brain. Cytokine expression was regionally specific since TNF-α levels were significantly elevated in cortex compared to hippocampus (57% greater) and IL-1β levels were elevated in hippocampus compared to cortical samples (126% greater). Increases in cytokine levels also were observed after irradiation of mouse BV-2 microglial cells. A series of electrophoretic mobility shift assays (EMSA) demonstrated that irradiation significantly increased activation of activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and cAMP response element-binding protein (CREB).Conclusion-The present study demonstrated that whole brain irradiation induces regionally specific pro-inflammatory environments through activation of AP-1, NF-κB, and CREB and overexpression of TNF-α, IL-1β, and MCP-1 in rat brain and may contribute to unique pathways for the radiation-induced impairments in tissue function.
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