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.
Highlights
BackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disease, showing increasing prevalence with age among the elderly population
Whereas less than 1% of AD cases are attributable to genetic mutations in the genes coding for amyloid precursor protein (APP), presenilin-1 (PS1), or presenilin-2 (PS2) that contribute to the early onset form of the disease, the vast majority of AD cases are sporadic, and have a later disease onset
Physical activity is correlated with attenuation of cognitive impairment, amelioration of agerelated changes in the brain, and reduced risk of dementia [76, 77]
Summary
BackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disease, showing increasing prevalence with age among the elderly population. Exercise in the form of wheel running was shown to lead to cognitive improvements, such as enhanced memory function, a rescue of synaptic plasticity, and an amelioration of some pathological features, including a decrease in levels of Aβ in some studies [10,11,12,13,14,15,16,17] The latter was proposed to be mediated through changes in APP processing [18] and an increase in clearance of Aβ [19], possibly resulting from an elevation of Aβ clearance proteins [20] and increased glymphatic clearance [21]. Exercise has been proposed to mitigate mitochondrial dysfunction [11, 26], delay disease-related white matter volume loss [27,28,29,30], reduce neuroinflammation [19, 21, 22, 31,32,33,34] and oxidative stress [10, 19, 35], repress neuronal cell death [36], and favor adult neurogenesis [17, 37,38,39,40]
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