β-细辛醚通过调控NMDA受体兴奋性和突触重塑抗阿尔茨海默病的作用机制研究

Previous works suggest that β-asarone may prevent synaptic loss and reverse cognitive deficits in Alzheimer's disease, but the mechanism still remains unknown. Here, we hypothesize that β-asarone may enhance synaptic density/plasticity through chronically inhibition of Ca2+ flux and calcium overload by regulating the activity of NMDA receptors, resulting in amelioration of neuronal death or apoptosis.. In this study, we will use combined approaches of transgenic animal models, electrophysiological recording, imaging, behavioral test, cellular and molecular biology to verify the above hypothesis. 1) to test if β-asarone can prevent learning and memory deficits as well as deposition of amyloid beta protein, tau protein phosphorylation. 2) using patch clamp records NMDA receptor currents, combined with other methods to explore the mechanism underlying inhibition of NMDA activity of β-asarone. 3) using confocal microscopy imaging to determine the density and morphology changes of dendritic spine, as well as dynamic of synaptic formation. By analyzing interaction between the NMDA receptor dependent calcium signaling, synaptogenesis and synaptic plasticity, we try to investigate the mechanism underlying the neuroprotection of β-asarone. It can be expected the project will clarify effect of β-asarone of down regulating NMDA excitotoxicity for treating or preventing learning and memory deficits in Alzheimer's disease. It has important scientific significance and practical significance.

石菖蒲活性成分β-细辛醚能有效改善阿尔兹海默(AD)病学习记忆功能损害和突触缺失，但作用机制尚不明确。.申请者提出科学假说：β-细辛醚通过抑制NMDA受体活性，改善胞内钙超载，调节cAMP/PKA—CREB—BDNF 信号通路，影响突触重塑和突触可塑性，改善AD病学习记忆功能障碍。.为验证以上假设，本研究将综合运用行为、电生理、激光共聚焦成像及分子细胞生物学技术，①验证β-细辛醚对AD病学习记忆功能损伤、Aβ沉积和Tau蛋白磷酸化的改善作用。②研究β-细辛醚抑制NMDA受体电流特点，结合药理学工具药和配体结合试验等，探明其抑制NMDA受体的机理。③研究β-细辛醚对神经发育、突触形成和消退、树突棘密度和形态动态变化的影响，及其干预NMDA受体依赖钙信号、突触重塑和突触可塑性交互作用的机理。本研究将阐明β-细辛醚抑制NMDA受体兴奋毒性抗AD病的机制，具有重要科学意义和现实意义。

石菖蒲活性成分β-细辛醚可有效改善阿尔兹海默病学习记忆功能的损害和突触缺失（synaptic loss），但作用机制尚不明确。本课题提出假说：细辛醚可能通过直接和/或间接调节NMDA受体活性，改善胞内Ca2+超载，改善突触密度减少和突触可塑性损伤，从而治疗AD病学习记忆功能的障碍。.课题采用行为学和电生理技术，验证了β-细辛醚对APP/PS1转基因鼠学习和记忆功能和突触损伤的保护作用。观察了β-细辛醚对NMDA受体电流、电压依赖性钙电流VDCC和胞内自由钙离子浓度[Ca2+]的抑制作用。并通过成像和电生理研究了β-细辛醚对突触形态和突触生成的影响。结果，β-细辛醚改善AD模型鼠的学习记忆功能，抑制NMDA受体功能，改善突触重塑与突触可塑性变化的紊乱。本课题对探明β-细辛醚抑制NMDA受体的靶点，调节突触重塑与，阐明β-细辛醚抑制NMDA兴奋毒性抗AD病的机制，具有重要科学意义和现实意义。