A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer’s disease

Abstract

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer's disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer's patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer's disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer's related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer's disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer's disease pathology by showing that capillary stalling is not decreased following exercise.

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimer’s disease mouse model

“…Such CBF reductions develop early in the pathogenesis of AD, when intervention would be most ideal ( 38 ). We previously showed that a small fraction of cortical capillaries is temporarily stalled at a four times higher rate in multiple mouse models of APP overexpression, as compared to WT mice ( 37, 39, 40 ). Furthermore, we found that administering an antibody against a neutrophil specific protein, Ly6G, led to a ~64% reduction in the incidence of capillary stalling and a ~17% increase in CBF.…”

Personalized treatment interventions: nonpharmacological and natural treatment strategies in Alzheimer’s disease

“…Both interval and continued exercise decreased the levels of hippocampal Aβ40 and Aβ42 levels, reduced lipid peroxidation and enhanced antioxidant defenses [23]. However, free running did not alleviate microvascular dysfunction [31], while, in another study voluntary exercise increased tissue oxygenation, which supports the metabolic demand of neurons [30]. Moreover, voluntary physical exercise mitigated the neurodegenerative changes in the brain such as disintegration of the pyramidal layer structure, neuronal loss, severe pericellular edema, and accumulation of amyloid and cerebral amyloid angiopathy [21].…”

“…Physical activity also influenced the brain already affected by plaques and tangles. For example, treadmill exercise prevented inflammatory events triggered by Aβ in mice hippocampus [29] and was associated with fewer cortical Aβ deposits [30], increased number of proliferating neuronal stem cells in the dentate gyrus, reduced hippocampal volume occupied by amyloid plaques [31], reversed the lipid peroxidation increase and restored the reduction in AChE activity [26], compared to sedentary controls. Both interval and continued exercise decreased the levels of hippocampal Aβ40 and Aβ42 levels, reduced lipid peroxidation and enhanced antioxidant defenses [23].…”

Exercise attenuates low back pain and alters epigenetic regulation in intervertebral discs in a mouse model

“…After 5-minute habitation to the enclosure, the total number of wheel's rotation was recorded during one hour to assess animal's running capability. A Wireless USB Hub (DIG-807, Med Associates, Inc.) and Wheel Manager Software (SOF-860, Med Associates, Inc.) were used for data collection [48,49]. The wheel was cleaned with soap and water before each new user.…”