IGF-1/GSK3β通路在有氧运动改善阿尔茨海默病中的作用与机制

A growing body of evidence suggests that exercise alleviates or prevents from cognitive declines induced by neurodegenerative disease, brain ageing or mental disease. However, little is known about the molecular mechanisms mediating the effect of exercise. Proper transport and distribution of mitochondria in axon and synapses are critical for the normal physiology of neurons, and mitochondrial dysfunction is associated with synaptic transmission and recongnition memory loss in AD and brain ageing. Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of AD, the extracellular senile plaques composed of β-amyloid and the intracellular neurofibrillary tangles formed from hyperphosphorylated tau. We have shown that aerobic exercise can increase the distribution of mitochondria in synapse by upregulation the levels of Kinesin heavy chain and light chain in APP/PS1 transgenic mice, thereby improving the synaptic structure and function. This purpose of this study is to determine the effects of aerobic exercise on IGF-1/GSK 3β signaling pathways in the hippocampus and cortex in APP/PS1 /Tau transgenic mice by behavioral testing paradigms, recording the changes of cortical and hippocampal ensemble neuronal activity and local field potentials, histological morphology, and molecular biological technique and so on. The results would to demonstrate aerobic exercise could regulate IGF-1/GSK 3β signaling pathways to rescue impaired synaptic plasticity, neuronal function and mitochondria dysfunction, which play a major role in learning and memory.

运动能够减轻并预防因神经退行疾病、脑老化、精神等因素引起的认知障碍，但运动是如何提高大脑功能来优化大脑的机制仍不清楚。线粒体损伤引起轴突转运异常是神经元突触功能减退及认知记忆功能受损的机制之一。GSK3β既与线粒体功能状态密切相关，又参与由APP生成Aβ以及tau蛋白过度磷酸化的过程。我们前期发现早期有氧运动干预可以上调AD小鼠线粒体顺向转运马达蛋白Kinesin表达，增加线粒体在突触分布，改善突触结构和功能。本项目拟以不同月龄的APP/PS1/Tau转基因小鼠为研究对象，经有氧运动干预后，应用行为学检测、电生理学、组织形态学、分子生物学等方法，观察有氧运动通过增加脑组织中IGF-1含量，抑制神经元GSK3β活性，降低AD脑内Aβ沉积及Tau蛋白过度磷酸化，改善线粒体功能，进而提高AD的神经元功能及认知记忆行为学能力。以期证明有氧运动通过调节IGF-1/GSK3β通路、早期改善线粒体功能、预防或延缓AD的发生、发展，为运动优化脑功能提供分子基础。

运动有助于预防或延缓AD发生、发展，但生物学作用机制尚不清楚。本课题以GSK 3β为中心，以不同月龄3×Tg-AD小鼠为AD模型，研究了有氧运动通过调节AD模型GSK 3β活性，改善线粒体功能，增加突触可塑性，提高认知记忆行为学能力的相关机制。研究发现在体水平该模型2月龄海马CA1区即出现theta时段gamma能量和棘波-涟漪波（sharp waves and ripples，SWR）时段低频gamma能量升高及神经元兴奋性改变；随月龄增加病理性改变加重。有氧运动明显降低AD模型不同月龄脑内Aβ和tau蛋白过度磷酸化，提高前额叶和海马CA1区theta时段gamma能量、theta-gamma耦合及SWR时段低频gamma能量，但对12月龄tau蛋白总量和gamma能量变化作用不明显。离体脑片水平发现该模型2月龄海马基础突触强度降低，突触自身稳态可塑性改变；至6月龄海马基础突触强度和长时程增强（long-term potentiation，LTP）受损、易化长时程抑制（long-term depression，LTD），海马CA3区和CA1区E/I ratio显著减小。有氧运动显著增加6月龄海马CA3区和CA1区E/I ratio，增强海马基础突触传递和LTP、减弱LTD。分子水平研究发现有氧运动减轻局部神经炎症，进而调节脑组织局部GSK 3β活性是改善该模型线粒体功能、增加突触形态和功能可塑性的机制之一，而有氧运动增加循环血液中IGF-1含量，与脑脊液中IGF-1的变化并不平行。GSK 3β活性调节更可能是运动通过减轻病理性Aβ激活的小胶质细胞和星型胶质细胞诱导的炎性反应而实现的。本研究结果为AD的早期非药物干预治疗提供了实验室证据，提示运动对AD的干预应尽早实施，即早发现、早干预。