Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid

BACKGROUND: Inflammation is associated with Aβ pathology in Alzheimer's disease (AD) and transgenic AD models. Previously, it has been demonstrated that chronic stimulation of the immune response induces pro-inflammatory cytokines IL-1β and TNF-α which contribute to neurodegeneration. However, recent evidence has shown that inducing the adaptive immune response reduces Aβ pathology and is neuroprotective. Low concentrations of IFN-γ modulate the adaptive immune response by directing microglia to differentiate to antigen presenting cells. Our objective was to determine if exercise could induce a shift from the immune profile in aged (17–19 months) Tg2576 mice to a response that reduces Aβ pathology. METHODS: TG (n = 29) and WT (n = 27) mice were divided into sedentary (SED) and exercised (RUN) groups. RUN animals were provided an in-cage running wheel for 3 weeks. Tissue was harvested and hippocampus and cortex dissected out. Quantitative data was analyzed using 2 × 2 ANOVA and student's t-tests. RESULTS: IL-1β and TNF-α were significantly greater in hippocampi from sedentary Tg2576 (TG(SED)) mice than in wildtype (WT(SED)) (p = 0.04, p = 0.006). Immune response proteins IFN-γ and MIP-1α are lower in TG(SED )mice than in WT(SED )(p = 0.03, p = 0.07). Following three weeks of voluntary wheel running, IL-1β and TNF-α decreased to levels indistinguishable from WT. Concurrently, IFN-γ and MIP-1α increased in TG(RUN). Increased CD40 and MHCII, markers of antigen presentation, were observed in TG(RUN )animals compared to TG(SED), as well as CD11c staining in and around plaques and vasculature. Additional vascular reactivity observed in TG(RUN )is consistent with an alternative activation immune pathway, involving perivascular macrophages. Significant decreases in soluble Aβ(40 )(p = 0.01) and soluble fibrillar Aβ (p = 0.01) were observed in the exercised transgenic animals. CONCLUSION: Exercise shifts the immune response from innate to an adaptive or alternative response. This shift in immune response coincides with a decrease in Aβ in advanced pathological states.