Interactions between stress and physical activity on Alzheimer's disease pathology

Abstract

Physical activity and stress are both environmental modifiers of Alzheimer's disease (AD) risk. Animal studies of physical activity in AD models have largely reported positive results, however benefits are not always observed in either cognitive or pathological outcomes and inconsistencies among findings remain. Studies using forced exercise may increase stress and mitigate some of the benefit of physical activity in AD models, while voluntary exercise regimens may not achieve optimal intensity to provide robust benefit. We evaluated the findings of studies of voluntary and forced exercise regimens in AD mouse models to determine the influence of stress, or the intensity of exercise needed to outweigh the negative effects of stress on AD measures. In addition, we show that chronic physical activity in a mouse model of AD can prevent the effects of acute restraint stress on Aβ levels in the hippocampus. Stress and physical activity have many overlapping and divergent effects on the body and some of the possible mechanisms through which physical activity may protect against stress-induced risk factors for AD are discussed. While the physiological effects of acute stress and acute exercise overlap, chronic effects of physical activity appear to directly oppose the effects of chronic stress on risk factors for AD. Further study is needed to identify optimal parameters for intensity, duration and frequency of physical activity to counterbalance effects of stress on the development and progression of AD.

Keywords: Alzheimer's disease; Amyloid; Exercise; Physical activity; Stress.

Fig. 1

Classification of Physical Activity. Acute physical activity refers to an individual bout of activity that can be part of the normal process of conducting daily business (normal daily physical activity) or it can be exercise which refers to a planned session of physical activity such as walking, jogging, bicycling, swimming, weight lifting or stretching intended to be part of a chronic physical activity program with the goal of improving health. Chronic physical activity is a regimen of exercise carried out over time with the goal of improving physical or psychological health. Exercise training is a chronic physical activity regimen of sufficient intensity, duration, and frequency to increases physical fitness. Sub-exercise training is a chronic physical activity regimen that is not of sufficient intensity, duration, or frequency to improve physical fitness, but may reduce psychological stress and improve psychological health.

Fig. 2

Effects of chronic exercise on acute restraint stress in female APP/PS1 mice. (A) Aβ levels in the hippocampus were measured every hour and change from baseline values were calculated in response to acute restraint stress in 4 month old female APP/PS1 mice. Total number of mice was 12, with n = 6 per group, however the microdialysis probe clogged in one mouse in the RUN group during restraint stress resulting in n = 5 for longitudinal analysis. Two way Repeated Measures ANOVA show significant interaction between group and time [F(21,189) = 3.663, p < 0.0001]. Simple main effects with Bonferroni correction for multiple comparisons indicate a significant increase from baseline in the SED group at hours 2, 5, 8, 9, 10 and 15 h from stress, while no significant change from baseline was seen in the RUN group. Between subjects comparisons show differences between groups at hour 10 (**p = 0.0095) and 15 (**p = 0.0051) following stress. (B) Mice in the RUN group had significantly lower concentrations in ISF Aβ in the hippocampus at baseline compared to SED group [unpaired t-test: t = 2.778, df = 10, p = 0.0195]. (C) Measures of citrate synthase activity in the soleus muscle were significantly higher in the RUN group compared to SED animals [unpaired t-test: t = 3.204, df = 10, p = 0.0094] indicating a significant exercise training effect following the 8-week exercise regimen.

Fig. 3

Acute and Chronic Effects of Stress and Exercise. Acute effects of exercise and stress overlap, but lead to divergent chronic adaptations that change risk for developing AD. The acute physiological effects of stress and exercise have several similar aspects that could lead to improvement or impairment in AD. Adaptive responses to chronic stress increase risk for AD, while the adaptive responses to chronic exercise decrease risk for AD.