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

Abstract

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.

Effect of treadmill exercise on PI3K/AKT/mTOR, autophagy, and Tau hyperphosphorylation in the cerebral cortex of NSE/htau23 transgenic mice

“…The phosphorylation of Ser404, Ser202, Thr231 and PHF-1, the phosphorylated residues of tau protein, was found to be increased in the Tg-CON group compared with that in the NonTg-CON group, whereas it was reduced in the Tg-TE group after the completion of the treadmill exercise. These findings are consistent with those of previous studies showing that, when transgenic mice with Alzheimer's disease were subjected to treadmill exercise, the phosphorylation of Ser404, Ser202 and Thr231 as phosphorylated residues of tau protein was reduced [30,50]. Furthermore, the analysis of cognitive ability in the underwater maze tests revealed that the Tg-CON group had an increased time and distance to locate the circular escape bar compared with the NonTg-CON, showing a decreased learning and memory capacity.…”

Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology

“…In agreement with this hypothesis, some groups have reported that voluntary or forced exercise changes the activity of various kinases in the hippocampus (e.g. PI3K/Akt, PKC, ERK, p38), even though their results are not always consistent (Chae et al, 2009;Chen and Russo-Neustadt, 2005;Leem et al, 2009). Similarly, our data indicate that long-term exercise significantly increases hippocampal BDNF, a neurotrophin that promotes synaptic plasticity and memory (Cunha et al, 2010;Heldt et al, 2007) and is known to play an important role in the mnesic effects of exercise Neeper et al, 1996;Vaynman et al, 2004Vaynman et al, , 2006.…”

Physical activity predicts gray matter volume in late adulthood

“…34 The addition of new cells requires increased nutrients, which are supplied by new vasculature. 35 In a mouse model of AD, exercising animals show a reduction in ␤-amyloid deposits, 36 reduced tau formation, 37 and superior learning rates compared to sedentary animals. 38 Our results are encouraging, but need to be interpreted in light of some important limitations.…”