半胱氨酰白三烯受体2对Aβ1-42诱导神经元损伤的调节及机制

β-amyloid deposition in Alzheimer's disease activated microglia, lead to injury of hippocampal neurons and cortex. It's quitely important to study the inflammatory mechanisms. We recently found that cysteinyl leukotriene receptor 2 (CysLT2 receptor) was closely related to the injury of neurons and microglial activation. The project intends to study: (1) Role of CysLT2 receptor in modulatation of neuron injury induced by Aβ1-42, and comparison of CysLT1 and CysLT2 receptor after injury. Observe the behavior changes, brain injury and release of inflammatory cytokines with treatment of antagonist. (2) Whether CysLT2 receptor mediated neural injury through microglia activation. To deal with neuron with microglia culture fluid, clarify role of CysLT2 receptor in regulation of neuron injury mediated by microglia which released some substances , as well as the interaction between receptor subtypes. The project will not only enhance the understanding of the CysLT receptor and the mechanisms of neuronal injury, but also provide new clues for AD-like injury with treatment of different antagonists.

阿尔茨海默病（AD）后Aβ沉积可活化小胶质细胞，导致海马、皮层等区域神经元损伤，研究其炎症调节机制具有重要意义。我们最近发现半胱氨酰白三烯受体2 （CysLT2受体）与神经元损伤及小胶质细胞激活有密切关联。本项目拟研究：（1）AD后CysLT2受体调节神经元损伤的作用，在整体及细胞水平比较Aβ1-42诱导损伤后CysLT2和CysLT1受体表达特点；用受体拮抗剂后，观察行为学改变、脑损伤变化及炎症因子释放。（2）CysLT2受体是否通过小胶质细胞诱导神经元损伤。通过小胶质细胞培养液处理神经元，阐明CysLT2受体介导小胶质细胞释放哪些物质调节神经元损伤，以及受体亚型间的相互影响。本项目不仅将加深CysLT受体及神经元损伤机制的理解，也为不同亚型拮抗剂防治AD样损伤提供新的线索。

本项目从整体和离体水平的大鼠阿尔茨海默病损伤模型，首次发现：（1）半胱氨酰白三烯受体2（CysLT2受体）拮抗剂HAMI 3379减轻Aβ诱导的学习记忆功能改变、神经元损伤，其机制与抑制星形胶质细胞增殖，小胶质细胞活化和增殖，半胱氨酰白三烯释放以及TNF-α、IL-1β等炎症因子释放有关；（2）Aβ脑室注射后，脑内半胱氨酰白三烯（CysLTs）释放增加，半胱氨酰白三烯受体2蛋白表达增加；（3）在离体培养的神经元，HAMI 3379（0.001-10 μΜ）可明显减轻Aβ诱导的细胞活性下降、LDH释放和细胞凋亡，机制与其抑制TNF-α、IL-1β释放有关；（4）Aβ诱导原代培养的神经元损伤，CysLT2受体表达上调，HAMI 3379或天然产物活性组分1,8-桉油素抑制半胱氨酰白三烯的产生，提示半胱氨酰白三烯可能通过激活CysLT2受体参与细胞损伤。上述结果证实CysLT2受体参与介导Aβ诱导神经元损伤的发生，可能成为阿尔茨海默病防治的潜在的新靶点。