MICROGLIAL NEURON SPECIFIC TOXIN

小胶质细胞构成中枢神经系统的免疫系统；这些细胞的不适当激活和由此产生的炎症与许多神经退行性疾病的进展有关，包括阿尔茨海默病（AD）和帕金森病（PD）。抑制小胶质细胞的激活是预防或至少延缓神经退行性变进展的明显途径。大规模、长期抑制大脑免疫系统的一个主要缺点是增加了对癌症和感染的易感性。在小胶质细胞产生和释放的许多神经毒性化合物中，有一种兴奋毒素可以激活NMDA受体，可能是一种神经元特异性毒素，对神经退行性疾病的进展至关重要。如果可以选择性地抑制这种毒素的产生和释放，就有可能针对参与神经元杀伤的主要小胶质细胞途径，同时保留参与预防癌症和感染的有益细胞毒性途径。本项目的目的是1)表征小胶质细胞衍生的神经元特异性毒素基底前脑胆碱能和中脑多巴胺能神经元培养物，这些培养物在AD和PD中优先死亡；2)表征参与小胶质细胞衍生的神经元特异性毒素产生的激活和抑制的途径。优先抑制神经元特异性毒素产生途径的药物是治疗神经退行性疾病的潜在药物。相反，对阿尔茨海默病和帕金森病有希望的药物将在这个模型系统中进行检查，看它们是否抑制神经元特异性毒素的产生或作用。

Microglia comprise the immune system of the central nervous system; inappropriate activation of these cells and the resultant inflammation has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's (PD) disease. Inhibition of microglial activation is an obvious approach to prevent orat least delay progression of neurodegeneration. A major expected drawback to large scale, long term inhibition of the brain's immune system is increased susceptibility to cancer and infection. Among the many neurotoxic compounds produced and released by microglia is an excitotoxin which activates NMDA receptors and may be a neuron-specific toxin critical for progression of neurodegenerative diseases. If production and release of this toxin can be selective inhibited, it should be possible to target the major microglial pathway involved in neuronal killing while preserving beneficial cytotoxic pathways involved in protecting against cancer and infection. The aims of this project are 1) to characterize the microglia-derived neuron-specific toxin basal forebrain cholinergic and mesencephalic dopaminergic neuronal cultures, the cultures which preferentially die in AD and PD; 2) to characterize pathways involved in the activation and inhibition of production of the microglia-derived neuron-specific toxin. Drugs that preferentially inhibit the neuron-specific toxin producing pathway are potential therapeutic agents against neurodegenerative disease. Conversely, drugs that show promise against AD and PD will be examined in this model system to see if they inhibit the production or action of the neuron- specific toxin.