Taylor D L, Diemel L T, Cuzner M L, Pocock J M
Cell Signalling Laboratory and Laboratory of Experimental Neuroinflammation, Department of Neuroinflammation, Division of Neurochemistry, Institute of Neurology, University College London, UK.
J Neurochem. 2002 Sep;82(5):1179-91. doi: 10.1046/j.1471-4159.2002.01062.x.
Regulation of microglial reactivity and neurotoxicity is critical for neuroprotection in neurodegenerative diseases. Here we report that microglia possess functional group II metabotropic glutamate receptors, expressing mRNA and receptor protein for mGlu2 and mGlu3, negatively coupled to adenylate cyclase. Two different agonists of these receptors were able to induce a neurotoxic microglial phenotype which was attenuated by a specific antagonist. Chromogranin A, a secretory peptide expressed in amyloid plaques in Alzheimer's disease, activates microglia to a reactive neurotoxic phenotype. Chromogranin A-induced microglial activation and subsequent neurotoxicity may also involve an underlying stimulation of group II metabotropic glutamate receptors since their inhibition reduced chromogranin A-induced microglial reactivity and neurotoxicity. These results show that selective inhibition of microglial group II metabotropic glutamate receptors has a positive impact on neuronal survival, and may prove a therapeutic target in Alzheimer's disease.
小胶质细胞反应性和神经毒性的调节对神经退行性疾病中的神经保护至关重要。在此我们报告，小胶质细胞具有功能性II型代谢型谷氨酸受体，表达mGlu2和mGlu3的mRNA及受体蛋白，与腺苷酸环化酶负偶联。这两种受体的两种不同激动剂能够诱导神经毒性小胶质细胞表型，该表型可被特异性拮抗剂减弱。嗜铬粒蛋白A是一种在阿尔茨海默病淀粉样斑块中表达的分泌肽，可将小胶质细胞激活为反应性神经毒性表型。嗜铬粒蛋白A诱导的小胶质细胞激活及随后的神经毒性可能也涉及对II型代谢型谷氨酸受体的潜在刺激，因为对其抑制可降低嗜铬粒蛋白A诱导的小胶质细胞反应性和神经毒性。这些结果表明，选择性抑制小胶质细胞II型代谢型谷氨酸受体对神经元存活有积极影响，可能成为阿尔茨海默病的治疗靶点。
