基于针灸抗炎作用防治阿尔茨海默病星形胶质细胞介导的β-淀粉样蛋白代谢机制研究

Astrocytes mediated β-amyloid protein metabolic disorder is the new-hot-spot of the pathological mechanisms of Alzheimer's disease. There is different between astrocytes mediated β-amyloid protein metabolic disorder and neurons mediated β-amyloid protein metabolic disorder. the former even is earlier than the latter. Astrocytes mediated β-amyloid protein metabolic disorders and the inflammatory cascade form a feedback amplification system, which increased Aβ neurotoxicity, resulting and accelerating in the occurrence and development of AD. This paper intends to work on the basis of preliminary studies to intraventricular injection of Aβ1-42 -induced AD rat model , using the relevant molecular biology techniques。For the first time with astrocyte -mediated β- amyloid protein metabolism as a starting point, to discuss the promotion effect or the inhibition effect to the activated astrocytes mediated Aβ generation and clearance. to discuss the relationship to the early onset of AD; to analysis their interaction with the inflammatory cascade playing the action of " double-edged sword " mechanism. In all, the research will provide the new information on improving the function of learning and memory by the treatment of acupuncture and moxibustion; further based on the anti-inflammatory effects of acupuncture, taking NF-kB as a target , explore acupuncture benign regulation of astrocyte - Aβ metabolism - inflammation cascades chain , for the better research on acupuncture multi-link, multi-target mechanism of AD prevention to provide more clues.

星形胶质细胞介导β-淀粉样蛋白的代谢紊乱是阿尔茨海默病病理机制的新热点，它既不同于神经元又早于神经元对Aβ的诱导。星形胶质细胞介导的β-淀粉样蛋白的代谢紊乱又与炎性级联反应形成反馈放大系统，加重Aβ神经毒性，导致并加速AD的发生与发展。本课题拟在前期研究工作基础上，以脑室内注射Aβ1-42诱导AD模型大鼠为对象，采用相关分子生物学技术，首次以星形胶质细胞介导β-淀粉样蛋白代谢为切入点，探讨被激活星形胶质细胞对Aβ生成，内化与降解的促进或抑制作用及其与AD早期发病之间的关系；及其与炎性级联反应相互作用，共同发挥"双刃剑"的作用机理，为深入揭示针灸改善学习记忆功能的作用机制提供全新资料；进一步基于针灸抗炎作用，以NF-kB为靶标，探讨针灸良性调控星形胶质细胞- - Aβ代谢- - 炎性级联反应链，为更好的研究针灸多环节、多靶点的防治AD作用机制提供更多的线索。

Aβ过度沉积与炎性反应均是阿尔茨海默病的重要病理特征，两者密切联系、相互影响，加速AD病理进程。以往认为Aβ过度沉积是由于Aβ过度生成，然Aβ代谢包括Aβ生成、Aβ内化与降解、Aβ清除，任何一个环节失常必然导致Aβ代谢平衡失稳。星形胶质细胞AC激活能反馈放大炎性级联反应，也可能参与介导Aβ代谢紊乱。本研究以脑室内注射Aβ1-42诱导AD模型大鼠为对象，采用相关分子生物学技术，探讨针灸在良性调控被激活星形胶质细胞与炎性级联反应的过程中，如何进一步介导Aβ生成、内化与降解及其改善学习记忆能力的作用机制。研究结果显示：1）注射Aβ1-42后确能导致海马神经元和星形胶质细胞超微结构的损伤。针灸治疗后虽神经元胞质和星形胶质细胞周边水肿仍较明显，但较模型组均有所减轻，且神经元内质网、核糖体未见明显异常。提示针灸治疗有助于改善Aβ1-42诱导阿尔茨海默病大鼠海马齿状回神经元和星形胶质细胞的超微病理变化。2）AD发生存在慢性炎性反应，且炎性因子在中枢和外周的变化趋势基本一致。针灸能够通过整体调节中枢和外周各类抗炎因子与促炎因子的失衡状态，有效改善AD症状。3）抑制Aβ的产生，促进Aβ的清除均是减轻AD病理损伤的有效途径，两者缺一不可。针灸治疗能通过降低BACE的分泌而抑制Aβ的产生，也能通过降低LPL、IDE、TTR、ApoE及α2M的表达，增强 Aβ酶降解系统降解作用，协同促进Aβ的代谢，有效抑制Aβ的生成和清除过多的Aβ，改善Aβ异常沉积现象。4）被激活的星形胶质细胞具有双重作用。针灸能抑制脑内TLR4/NF-kB炎性信号通路，减少血清和海马区促炎症因子的含量，降低脑内APP水平；同时也能调控星形胶质细胞与NF-kB、抑炎性因子IL-10的相互作用，荧光双标初步显示针灸通过双向调节作用平衡了AC在AD病理进程中的双刃剑作用，重在放大发挥其对神经元的保护作用。研究充分证实了针灸能够多环节、多靶点的改善老年性痴呆发病过程中的星形胶质细胞-Aβ代谢-炎性反应的不同阶段，对针灸防治老年性痴呆及预防其他神经退行性疾病有着重要的意义。