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The Journal of Neuroscience, April 27, 2005, 25(17):4217-4221; doi:10.1523/JNEUROSCI.0496-05.2005
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BRIEF COMMUNICATION
Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease
Paul A. Adlard,
Victoria M. Perreau, *
Viorela Pop, * and
Carl W. Cotman
Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697-4540
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- (A) 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 A1-40 (35%; p = 0.005) and A1-42 (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  -C-terminal fragment (-CTF), 54% and p = 0.04; for -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.
Key words: Alzheimer's disease; exercise; amyloid; transgenic; APP; TgCRND8
Received Nov 29, 2004;
revised March 2, 2005;
accepted March 15, 2005.
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