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 ... -  《-》

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 ... -  《-》

Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice.

Wu M ，Shi H ，He Y ，Yuan L ，Qu X ，Zhang J ，Wang Z ，Cai H ，Qi J ... -  《-》

Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation.

Alzheimer's disease (AD) is a progressive neurodegenerative disease clinically characterized by learning and memory function deterioration. While it is well established that exercise can improve cognitive performance in AD, there have been few basic cellular and molecular mechanisms research performed to test the interaction between exercise and AD. In this study, we aimed at investigating whether treadmill exercise improves learning and memory function in APP/PS1 transgenic mouse model of Alzheimer's disease by enhancing long-term potentiation (LTP) and up-regulation of brain-derived neurotrophic factor (BDNF) mRNA expression. Our results show that, in comparison to wild type mice, transgenic mice were characterized by impaired learning and memory function, LTP deficits and increased BDNF mRNA levels. Treadmill exercise enhanced learning and memory function not only in wild type mice but also in APP/PS1 mice paralleled by LTP. However, BDNF has emerged as a crucial regulator of synaptic plasticity mechanisms underlying learning and memory in wild-type mice, but not in APP/PS1 mice. Hence, this investigation demonstrates that treadmill exercise is an effective therapeutic that alleviate learning and memory decline in APP/PS1 mouse model, and enhanced LTP maybe a cellular mechanism involved in neuropathological course of AD and cognitive improvement induced by exercise.

Liu HL ，Zhao G ，Cai K ，Zhao HH ，Shi LD ... -  《-》

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 ... -  《-》