Repression of tau hyperphosphorylation by chronic endurance exercise in aged transgenic mouse model of tauopathies.

The present study was undertaken to investigate whether chronic endurance exercise affects tau phosphorylation levels in the brain with Alzheimer's disease (AD)-like pathology. To address this, the transgenic (Tg) mouse model of tauopathies, Tg-NSE/htau23, which expresses human tau23 in the brain, was chosen. Animals were subjected to chronic exercise for 3 months from 16 months of age. The exercised Tg mouse groups were treadmill run at speeds of 12 m/min (intermediate exercise group) or 19 m/min (high exercise group) for 1 hr/day, 5 days/week, during the 3-month period. Chronic endurance exercise in Tg mice increased the expression of Cu/Zn-superoxide dismutase (SOD) and catalase, and also their enzymatic activities in the brain. In parallel, chronic exercise in Tg mice up-regulated the expression of phospho-PKCalpha, phospho-AKT, and phospho-PI3K, and down-regulated the expressions of phospho-PKA, phosphor-p38, phospho-JNK, and phospho-ERK. Moreover, chronic exercise up-regulated both cytosolic and nuclear levels of beta-catenin, and the expression of T-cell factor-4 (Tcf-4) and cyclin D1 in the brain. As a consequence of such changes, the levels of phospho-tau in the brain of Tg mice were markedly decreased after exercise. Immunohistochemical analysis showed an exercised-induced decrease of the phospho-tau levels in the CA3 subregion of the hippocampus. These results suggest that chronic endurance exercise may provide a therapeutic potential to alleviate the tau pathology.