Long-term treadmill exercise inhibits the progression of Alzheimer's disease-like neuropathology in the hippocampus of APP/PS1 transgenic mice.

Previously our study has demonstrated that long-term treadmill exercise improved cognitive deficit in APP/PS1 transgenic mice of Alzheimer's disease (AD) paralleled by enhanced long-term potentiation (LTP). The present study was undertaken to further investigate whether the treadmill running could inhibit the progression of Alzheimer's disease (AD)-like neuropathology in hippocampus of the APP/PS1 mouse models of AD, and to define a potential molecular mechanism underlying the exercise-induced reduction in AD-like neuropathology. Five months of treadmill exercise resulted in a robust reduction in β-amyloid (Aβ) deposition and tau phosphorylation in the hippocampus of APP/PS1 mice. This was accompanied by a significant decrease in APP phosphorylation and PS1 expression. We also observed GSK3, rather than CDK5, was inhibited by treadmill exercise. These results indicate that treadmill exercise is sufficient to inhibit the progression of AD-like neuropathology in the hippocampus of APP/PS1 transgenic mouse model, and may mediate APP processing in favor of reduced Aβ deposition. In addition, we demonstrate that treadmill exercise attenuates AD-like neuropathology in AD transgenic mice via a GSK3 dependent signaling pathway.

Liu HL ，Zhao G ，Zhang H ，Shi LD ... -  《-》

Treadmill exercise enhances synaptic plasticity, but does not alter β-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice.

Several studies reveal that the beneficial effects of exercise interventions are dependent on the progression of Alzheimer's disease (AD). We have previously shown that long-term treadmill exercise begun before the onset of β-amyloid (Aβ) pathology prevents the deficits of cognition and long-term potentiation (LTP) in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice (8 months of age) paralleled by the reduction of soluble Aβ levels and Aβ deposition in the hippocampus. In the present study, treadmill exercise was initiated at a developed Aβ deposition stage in order to further investigate whether or not treadmill exercise in this phase can delay the progression of AD in aged APP/PS1 mice (17 months of age). Our results show that 5-month treadmill exercise ameliorates the impairment of spatial learning and memory with age paralleled by synaptic plasticity enhancement in aged APP/PS1 mice. In addition, exercise-induced enhancement of synaptic plasticity was accompanied by a significant reduction of soluble Aβ levels rather than Aβ plaque deposition. Therefore, the investigation demonstrates that long-term treadmill exercise has beneficial effects on cognition and synaptic plasticity even when the brain has developed Aβ deposition, and changes in soluble Aβ levels rather than Aβ plaque deposition may contribute to exercise-induced benefits.

Zhao G ，Liu HL ，Zhang H ，Tong XJ ... -  《-》

Treadmill exercise decreases β-amyloid burden in APP/PS1 transgenic mice involving regulation of the unfolded protein response.

The accumulation of β-amyloid protein (Aβ) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). Overactivation of the unfolded protein response (UPR) signaling has been reported to lead to β-amyloidogenesis. The current study aimed to investigate the effects of treadmill exercise on UPR signaling and the Aβ production and to demonstrate whether exercise-induced Aβ reduction was associated with changes in UPR signaling. Three-month old male APP/PS1 transgenic and wild-type mice were subjected to treadmill exercise for 3 months. At the end of exercise (6 months old), the levels of Aβ plaques and soluble forms of Aβ, and proteins involve in the unfolded protein response (UPR) were analyzed in the hippocampus. Three months of treadmill exercise resulted in a robust reduction in Aβ plaques and soluble forms of Aβ in the hippocampus of APP/PS1 mice. This was accompanied by a significant decrease in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and presenilin-1 (PS1) expression. Meanwhile, we found that treadmill exercise down-regulated the expression of GRP78 and inhibited activation of PERK, eIF2α, and ATF4, reflecting the involvement of the UPR signaling. Overall, our findings suggest that treadmill exercise may suppresse the overactivation of the UPR signaling as well as inhibit the amyloidogenic pathway in APP/PS1 mice, thus may serve as an useful approach for the prevention and treatment of AD.

Xia J ，Li B ，Yin L ，Zhao N ，Yan Q ，Xu B ... -  《-》

Evaluation of Neuropathological Effects of a High-Fat Diet in a Presymptomatic Alzheimer's Disease Stage in APP/PS1 Mice.

Ettcheto M ，Petrov D ，Pedrós I ，Alva N ，Carbonell T ，Beas-Zarate C ，Pallas M ，Auladell C ，Folch J ，Camins A ... -  《-》

Moderate-Intensity Treadmill Exercise Regulates GSK3α/β Activity in the Cortex and Hippocampus of APP/PS1 Transgenic Mice.

Han P ，Gu B ，Mu L ，Yu JG ，Zhao L ... -  《Journal of Integrative Neuroscience》