The Differential Effect of Treadmill Exercise Intensity on Hippocampal Soluble Aβ and Lipid Metabolism in APP/PS1 Mice

Alzheimer's disease (AD) is characterized clinically by progressive impairments in learning and memory. Accumulating evidence suggests that regular exercise plays a neuroprotective role in aging-associated memory loss. Our previous study has confirmed that long-term treadmill exercise initiated either before or during the onset of β-amyloid (Aβ) pathology, was beneficial for reducing the levels of soluble Aβ and further improved cognition. In this study, in APP/PS1 mice, we assessed changes in soluble Aβ, and various blood biochemistry and molecular biological indices to assess whether exercise modulated lipid metabolism and thereby decelerated AD progression. Our results show that long-term treadmill exercise reduced the total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, and increased the level of high-density lipoprotein cholesterol. Exercise also decreased the levels of soluble Aβ1-40 and Aβ1-42, down-regulated retinoid X receptor expression, and up-regulated liver X receptor, Apolipoprotein E, Low density lipoprotein receptor, Low density lipoprotein receptor-related protein 1, and ATP-binding cassette transporter A1 expression. This indicates that long-term treadmill exercise alters the lipoprotein content, increases lipid metabolism and cholesterol transportation, reduces the soluble Aβ, and therein plays an important neuroprotective role and delays AD progression. We further show that medium exercise intensity (60%–70% of maximal oxygen uptake) was more efficacious in increasing lipid metabolism and reducing blood lipid levels and soluble Aβ levels, than low-intensity exercise (45–55% of maximal oxygen uptake). This research has broad prospects and implications, and offers a theoretical basis for the prevention of AD.