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.

Background Human studies on exercise, cognition, and apolipoprotein E (APOE) genotype show that ε4 carriers may benefit from regular physical activity. Methods We examined voluntary wheel-running, memory, and hippocampal plasticity in APOE ε3 and APOE ε4 transgenic mice at 10–12 months of age. Results Sedentary ε4 mice exhibited deficits in cognition on the radial-arm water maze (RAWM), a task dependent on the hippocampus. Six weeks of wheel-running in ε4 mice resulted in improvements on the RAWM to the level of ε3 mice. Hippocampal brain-derived neurotrophic factor (BDNF) levels were similar in ε3 and ε4 mice, and after exercise BDNF was similarly increased in both ε3 and ε4 mice. In sedentary ε4 mice, tyrosine kinase B (Trk B) receptors were reduced by 50%. Exercise restored Trk B in ε4 mice to the level of ε3 mice, and in ε4 mice, exercise dramatically increased synaptophysin, a marker of synaptic function. Conclusions Our results support the hypothesis that exercise can improve cognitive function, particularly in ε4 carriers.

Exercise is a treatment paradigm that can ameliorate cognitive dysfunction in Alzheimer disease (AD) and AD mouse models. Since exercise is also known to alter the peripheral immune response, one potential mechanism for the cognitive improvement following exercise may be by modulating the inflammatory repertoire in the central nervous system. We investigated the effects of voluntary exercise in the Tg2576 mouse model of AD at a time-point at which pathology has already developed. Inflammatory mRNA markers are increased in sedentary Tg2576 mice versus non-transgenic controls. We demonstrate that short-term voluntary wheel running improved spatial learning in aged transgenic mice as compared to sedentary Tg2576 controls. Inflammatory profiles of the Tg2576 and non-transgenic mice were different following exercise with the non-transgenic mice showing a broader response as compared to the Tg2576. Notably, exercising Tg2576 exhibited increases in a few markers including CXCL1 and CXCL12, two chemokines that may affect cognition.

No abstract

If begun early in life, exercise effectively reduces the development of cognitive deficits in transgenic mouse models of Alzheimer's disease (AD). However, the effectiveness of exercise, once the cognitive impairments are established, is not as clear. In terms of translating research in animal models to treatments involving exercise in Alzheimer's disease patients, it is critical to evaluate exercise intervention at time points that address not only prevention, but also treatment of cognitive decline. We provided exercise wheels to Tg2576 (TG) (n=12) and C57BL6 (WT) (n=17) mice at 16-18 months of age for three weeks. At this age animals have significant cognitive impairment and neuropathology consistent with AD. Age matched sedentary TG (n=13) and WT (n=12) mice were also included, as well as groups provided access to an immobile wheel (TG n=9, WT n=12). After three weeks, animals were evaluated in a radial arm water maze. Significant impairments were observed in the sedentary TG mice compared to WT in reference/long-term and working/short-term memory, as well as in probe trials. Exercised TG mice demonstrated improvements in memory, which made them indistinguishable from WT mice on all tasks. In addition, animals provided with an immobile wheel exhibited improvement in some, but not all cognitive measures. Our findings demonstrate that exercise can improve cognitive performance in a mouse model of AD even if applied after the development of pathology.