星形胶质细胞对Tau蛋白磷酸化和空间记忆能力的双相性变化及机制

发布时间：2018-06-24 07:30

本文选题：fluorocitrate + 阿尔茨海默病　；参考：《华中科技大学》2012年博士论文

【摘要】：背景：脑内神经元与胶质细胞的交互作用可能有多种非常重要的功能。神经元与胶质细胞有着类似于兴奋性突触上的LTP(突触可塑性的特征)样的活性依赖性修饰。在脊髓背侧角星行胶质细胞作为感应和维持病理性疼痛一个角色,归因于炎性反应或者神经损伤。神经损伤时,脊髓胶质细胞的密度增加,用fluorocitrate抑制有活性的脊髓胶质细胞,阻断了痛觉过敏和痛觉异常。星形胶质细胞参与了Ap,提供营养给神经元,并充当了一个Aβ聚集保护屏障。谷氨酸的动态平衡促成了星形胶质细胞介导调节神经元的功能。氟代柠檬酸(Fluorocitrate, FC)选择性抑制星形胶质细胞的乌头酸酶来调节星形胶质细胞三羧酸循环。然而FC损害星形胶质细胞后,是否影响tau蛋白磷酸化水平和空间记忆能力及其机制尚不明确。目的：探讨FC给药1h和48h后,对星形胶质细胞功能的影响,及星形胶质细胞功能改变对tau磷酸化水平及动物空间记忆能力的作用及机制。方法：本实验采用侧脑室定位注射fluorocitrate给药方式,通过电生理的方法记录fluorocitrate作用于星形胶质细胞1h时LTP水平,Morris水迷宫检测fluorocitrate作用于星形胶质细胞48h时大鼠的空间记忆能力,采用免疫印迹(Western blotting)检测大鼠海马tau的过度磷酸化、与tau蛋白磷酸化水平的相关磷酸激酶和磷酸酯酶的活性和突触蛋白的表达水平。在原代星形胶质细胞和神经元中,fluorocitrate作用于星形胶质细胞,检测tau蛋白磷酸化水平及相关磷酸酯酶的活性和突触蛋白的表达水平。结果：Fluorocitrate作用于星形胶质细胞1h,可导致星形胶质细胞功能受损,tau过度磷酸化和LTP缺陷；给药48h,星形胶质细胞激活,tau磷酸化水平降低,空间记忆能力改善。PP2A和AKT的活性从给药1h时下降,48h时无明显改变。FC给药1h时,突触相关蛋白GluR2、PSD93和PSD95的表达水平下降,但FC处理48h突触相关蛋白GluR2、PSD93和PSD95的表达水平升高。即早基因CREB和Arc表达水平在给药处理1h和48h时,均降低。结论：星形胶质细胞通过调节神经元突触相关蛋白和tau磷酸化水平,而调节动物的空间记忆能力。
[Abstract]:Background: the interaction of neurons in the brain and glia may have many very important functions. Neurons and glial cells have active dependent modification of LTP like synaptic plasticity. Glial cells in the dorsal horn of the spinal cord are used as a role in induction and maintenance of pathological pain. In the inflammatory response or nerve injury. The density of the spinal glial cells increases in the spinal cord and inhibits the active spinal glial cells with fluorocitrate, blocking the hyperalgesia and abnormal pain. Astrocytes participate in the Ap, provide nutrients to neurons, and act as a protective barrier to A beta. The dynamic balance of glutamic acid is facilitated. Astrocytes regulate the function of neurons. Fluorocitrate (FC) selectively inhibits astrocytes of astrocytes to regulate astrocyte three carboxylic acid cycle. However, the effect of FC damage on astrocytes is not clear and the mechanism of tau protein phosphorylation and spatial memory and its mechanism are not yet clear.
Objective: To investigate the effect of FC administration of 1H and 48h on the function of astrocytes and the effect of astrocyte function changes on the phosphorylation level of tau and the spatial memory ability of animals.
Methods: in this experiment, fluorocitrate was injected into the lateral ventricle, and the LTP level was recorded by fluorocitrate in astrocyte 1H by electrophysiological method. The spatial memory ability of fluorocitrate in astrocytes 48h was detected by Morris water maze, and Western blot (Western blotting) was used to detect the rats. Over phosphorylation of tau in the hippocampus, the activity of phosphokinase and phosphatase related to the level of tau protein phosphorylation and the expression level of synaptic proteins. In the primary astrocytes and neurons, fluorocitrate acts on astrocytes to detect the level of phosphorylation of tau protein and the activity of related phosphatase and the expression of synaptic proteins. Level.
Results: Fluorocitrate acts on astrocyte 1H, which can cause damage to astrocytes, tau overphosphorylation and LTP deficiency, 48h, astrocytes activation, tau phosphorylation level decreased, spatial memory ability to improve the activity of.PP2A and AKT from the dosage of 1H, and 48h did not change the.FC drug 1H, synapse related The expression level of protein GluR2, PSD93 and PSD95 decreased, but the expression level of 48h synapse related protein GluR2, PSD93 and PSD95 increased by FC. That is, the expression level of early gene CREB and Arc decreased in the dosing process 1H and 48h.
Conclusion: astrocytes regulate the spatial memory ability of animals by regulating the synapse related protein and tau phosphorylation level.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R363

【相似文献】