Tau蛋白异常聚积引起神经细胞退变的分子机制研究

Intracellular tau accumulation plays a crucial role in over 20 neurodegenerative disorders (collectively called “tauopathies”), in which tau accumulation is positively correlated with the progression of neurodegeneration and functional impairments. However, the molecular mechanism underlying tau-induced neurodegeneration is not fully understood and there is no effective strategy to arrest the progression of neurodegeneration. We have recently found that tau accumulation upregulates pro-inflammatory responses and decreases the expression level of NMDAR subunits with activation of STAT1, a transcriptional activator that can promote inflammatory response. We speculate that STAT1 activation may mediate the neurodegenerative effects induced by tau accumulation. In the present study, we will first confirm the essential role of STAT1 activation in tau-induced neurodegeneration in primary hippocampal neurons and in the mouse brains. Then, we will investigate how tau accumulation activates STAT1 and how STAT1 activation mediates tau-induced neurodegeneration. The results will reveal novel mechanisms underlying tau-induced neurodegeneration, by which to provide new molecular targets for intervention of neurodegenerative disorders.

细胞内tau蛋白聚积参与20余种神经退行性变性病（统称为“tau病”），且与其神经退变进程和功能障碍正相关，但tau聚积引起神经退变的分子机制尚不清楚。申请者最近发现，过表达tau蛋白升高促炎因子、降低NMDAR亚基的水平，同时伴有转录激活因子-1（STAT1）的显著上调。STAT1可促进炎症因子合成，而慢性炎症又是多种神经退行性疾病发生发展的重要事件。鉴于此，申请者推测，STAT1可能通过促进炎症反应和抑制突触蛋白表达，介导tau蛋白聚积引起的神经退变。本项目拟联合运用特异类型神经细胞基因敲除，细胞、生化分子生物学和电生理技术，在原代神经元、C57和tau转基因小鼠，确定STAT1激活在tau蛋白聚积所致神经退变中的关键作用；阐明tau聚积激活STAT1以及STAT1激活后介导tau蛋白毒性的分子机制。研究结果将揭示“tau病”神经退变的新机制，为药物研发提供新分子靶标。

细胞内tau蛋白聚积参与20余种神经退行性变性病（统称为“tau病”），且与其神经退变进程和功能障碍正相关，但tau聚积引起神经退变的分子机制尚不清楚。申请者最近发现，过表达tau蛋白升高促炎因子、降低NMDAR亚基的水平，同时伴有转录激活因子-1（STAT1）的显著上调。STAT1可促进炎症因子合成，而慢性炎症又是多种神经退行性疾病发生发展的重要事件。鉴于此，申请者推测，STAT1可能通过促进炎症反应和抑制突触蛋白表达，介导tau蛋白聚积引起的神经退变。本项目拟联合运用特异类型神经细胞基因敲除，细胞、生化分子生物学和电生理技术，在原代神经元、C57和tau转基因小鼠，确定STAT1激活在tau蛋白聚积所致神经退变中的关键作用；阐明tau聚积激活STAT1以及STAT1激活后介导tau蛋白毒性的分子机制。研究结果将揭示“tau病”神经退变的新机制，为药物研发提供新分子靶标。