ABSTRACT
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 ß-amyloid (Aß) 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 Aß deposition. In addition, we demonstrate that treadmill exercise attenuates AD-like neuropathology in AD transgenic mice via a GSK3 dependent signaling pathway.
Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/therapy , Hippocampus/pathology , Physical Conditioning, Animal , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Cyclin-Dependent Kinase 5/metabolism , Disease Models, Animal , Female , Glycogen Synthase Kinase 3/metabolism , Hippocampus/physiopathology , Humans , Mice, Inbred C57BL , Mice, Transgenic , Motor Activity/physiology , Phosphorylation/physiology , Plaque, Amyloid/physiopathology , Plaque, Amyloid/prevention & control , Presenilin-1/genetics , Presenilin-1/metabolism , Random Allocation , Signal Transduction/physiology , Time Factors , tau Proteins/metabolismABSTRACT
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.
Subject(s)
Alzheimer Disease/physiopathology , Hippocampus/physiopathology , Long-Term Potentiation/physiology , Maze Learning/physiology , Memory/physiology , Physical Conditioning, Animal/physiology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Electrophysiology , Hippocampus/metabolism , Mice , Mice, Transgenic , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Spatial Behavior/physiologyABSTRACT
OBJECTIVE: To estimate the effect of aluminum on hippocampal intracellular Ca²+ concentration and expression of phospholipase C (PLC) and NMDA receptor α (NMDARα) genes in hippocampus as well as the neural behaviors in weaning rats through subchronic exposure in order to explore the mechanism which aluminum impaired the ability of learning and memory of central nervous system development. METHODS: Weaning Wistar rats were randomly divided into four groups based on their body weight. Aluminium chloride was administered by water at the doses of 0.2%, 0.4% and 0.6% (m/v) for 90 days. Platform experiment was used to detect the activity of learning and memory. Fura-2/AM calcium ions fluorescence indicator was used to measure Ca²+ concentration in hippocampal neurons. Western blot method was used to detect the expressions of PLC and NMDARα genes. RESULTS: The incubation of rats in platform experiment [(232.20 ± 57.45), (35.00 ± 9.37), (16.10 ± 5.57) s] shortened while increase of mistake times (1.10 ± 0.74, 2.20 ± 0.92, 3.40 ± 1.51) was significantly associated with the dose of aluminum (P < 0.01). The Ca(2+) concentration decreased significantly in the rats of aluminum exposed groups (P < 0.01). The expression of PLC and NMDARα in aluminum exposed groups (0.30 ± 0.06, 0.18 ± 0.04, 0.16 ± 0.03; 0.38 ± 0.03, 0.32 ± 0.02, 0.25 ± 0.02) decreased significantly compared with that in the control group (0.47 ± 0.07, 0.48 ± 0.04) (P < 0.01) and there was a dose-effect relationship in the NMDARα expression. CONCLUSION: Subchronic exposure of aluminium could impair the ability of learning and memory in rats during development, inhibit the expression of NMDARα and PLC and reduce Ca²+ concentration, suggesting that the disorder of Ca²+ signaling system might be one of mechanisms of aluminium damaging the ability of learning and memory.
