mGlu受体在阿尔茨海默病中的作用及机制研究

发布时间：2018-02-26 08:58

本文关键词： 代谢性谷氨酸受体 β-淀粉样蛋白阿尔茨海默病 LTD Caspase　出处：《宁波大学》2012年硕士论文　论文类型：学位论文

【摘要】：目的：研究mGlu受体在阿尔茨海默病早期病理机制中的作用，并探讨Aβ介导的突触可塑性调制中的神经元内Caspase、p38MAPK、TACE、mTOR等信号通路的作用，为发现新型的药物靶点、治疗阿尔茨海默病提供理论和实验依据。方法：所有实验均在横切脑片的海马齿状回或CA1区进行。用3周龄wistar雄性大鼠快速断头后制成350微米脑片，并置于含有95%氧气饱和的人工脑脊液的孵育槽内，，室温下孵育一小时，然后将脑片转移到记录槽中，在海马齿状回或CA1区，使用标准电生理技术记录场兴奋性突触后电位和LTD。记录的fEPSP峰值用pClamp软件分析，用基础水平的相对百分数形式表示LTD的幅度。LTD值以均数±标准误(means±S.E.M.)表示，并进行双尾t检验和单因素方差分析（ANOVA）。结果：在海马齿状回和CA1区，强LFS刺激能诱导产生LTD，弱LFS则不能，但在可溶性Aβ寡聚体的参与下，弱LFS可诱导出稳定的LTD。NMDAR特异性拮抗剂D-AP5不能阻断这种Aβ介导的LTD增强，而相反的，mGluR受体拮抗剂LY341495可阻断这种LTD。另外caspase抑制剂、p38MAPK抑制剂SB203580、PTP抑制剂氧化苯胂、均能逆转Aβ介导的LTD增强，而mTOR抑制剂Rapamycin和TACE抑制剂TAPI-2没有明显作用。结论：可溶性Aβ寡聚体能增强弱LFS诱导的LTD，且这种增强作用是由mGluR参与的，而NMDAR不参与Aβ对LTD的增强。Aβ对LTD的增强作用可能涉及神经元内Caspase、p38、PTP等信号通路的参与。提示这些信号通路的胞内激酶可能是治疗阿尔茨海默病的潜在靶点。
[Abstract]:Aim: to study the role of mGlu receptor in the early pathological mechanism of Alzheimer's disease, and to explore the role of Caspasep38MAPKnTOR and other signaling pathways in synaptic plasticity modulation mediated by A 尾 in order to find new drug targets. To provide theoretical and experimental evidence for the treatment of Alzheimer's disease. Methods: all the experiments were carried out in the dentate gyrus or CA1 region of the transected brain slices. Three week-old male wistar rats were quickly decapitated into 350micron brain slices and placed in incubators with artificial cerebrospinal fluid (CSF) containing 95% oxygen saturation. After incubating at room temperature for one hour, the brain slices were transferred to the recording trough, and the excitatory postsynaptic potential and the peak value of fEPSP recorded in the dentate gyrus or CA1 region were recorded using standard electrophysiological techniques. The recorded peak values of fEPSP were analyzed by pClamp software. The amplitude of LTD was expressed by the relative percentage of basic level. The value of LTD was expressed as mean 卤standard error means 卤S.E.M., and double tail t test and single factor ANOVAA analysis were performed. Results: in hippocampal dentate gyrus and CA1 region, strong LFS stimulation could induce LTD, while weak LFS could not, but weak LFS could induce stable LTD.NMDAR specific antagonist D-AP5 to block the A 尾 -mediated LTD enhancement, with the participation of soluble A 尾 oligomer. On the other hand, caspase inhibitor, SB203580 PTP inhibitor, could reverse the A 尾 -mediated LTD enhancement, but mTOR inhibitor Rapamycin and TACE inhibitor TAPI-2 had no obvious effect. Conclusion: soluble A 尾 oligomerization can enhance LTD induced by weak LFS, and this enhancement is mediated by mGluR. NMDAR does not participate in the enhancement of LTD by A 尾. The enhancement of LTD by A 尾 may involve the involvement of signal pathways such as Caspase p38 PTP in neurons, suggesting that the intracellular kinase of these signaling pathways may be a potential target for the treatment of Alzheimer's disease.
【学位授予单位】：宁波大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R749.16

【参考文献】