Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (Abeta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical Abeta1-40 (35%; p = 0.005) and Abeta1-42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant (p < 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.

Figure 1.

The effect of exercise on Aβ load in three different brain regions of TgCRND8 mice. Exercising animals show a significant (^*) reduction in Aβ immunoreactivity in the frontal cortex (p = 0.018) and cortex at the level of the hippocampus (p = 0.0003). There is also a decrease in Aβ in the hippocampus of exercising animals (p = 0.06). The photomicrograph shows a representative section from both groups. Scale bar, 200 μm. Error bars indicate ± SE.

Figure 2.

Representative Western blot data from four animals showing no difference in APP or β-actin but showing significant (p < 0.04) reductions in both the α-CTF and β-CTF in the exercising animals compared with the sedentary animals.

Figure 3.

The effect of exercise on Morris water maze performance. Average escape latencies for sedentary and exercising TgCRND8 animals in the Morris water maze are shown. Exercised animals show improved performance across the time course, with significant differences present on the first 3 d of trials, compared with the sedentary animals (^*p < 0.02). Error bars indicate ± SE.