Cell Signalling Laboratory, Department of Neuroinflammation, UCL Institute of Neurology, London, UK.
J Neurochem. 2010 Jan;112(2):552-63. doi: 10.1111/j.1471-4159.2009.06485.x. Epub 2009 Nov 6.
Microglial activation can lead to microglial apoptosis, which may serve to remove highly reactive and possibly neurotoxic microglia. However the loss of microglia may have consequences for future recovery, protection and repair. P53, a nuclear phosphoprotein transcription factor, is critical for activating the expression of genes involved in cell-cycle arrest and stress-induced apoptosis. In neurodegenerative diseases the expression of p53 is significantly increased in glial cells, and microglial numbers fall. Following activation with chromogranin A (100 nM), or beta-amyloid(25-35), (10 microM), microglia became apoptotic. Furthermore, p53 expression was enhanced, peaking at 4-6 h after exposure to activators. The p53 transcription inhibitor, pifithrin-alpha, (10 microM) significantly reduced the expression of p53 in microglia and significantly modulated the levels of microglial apoptosis induced by activation. Lithium chloride (5 mM), which can modulate p53-mediated pathways, also reduced p53 expression and reduced microglial apoptosis suggesting glycogen synthase kinase-3 plays a role. Regulating p53 pathways modulated microglial inducible nitric oxide synthase expression and tumour necrosis factor alpha secretion. Inhibiting p53 mediated microglial apoptosis prevented microglial neurotoxicity suggesting targeting of p53-mediated pathways in microglia may have therapeutic benefit in Alzheimer's disease.
小胶质细胞的激活可导致小胶质细胞凋亡，这可能有助于清除高度活跃和可能神经毒性的小胶质细胞。然而，小胶质细胞的缺失可能会对未来的恢复、保护和修复产生影响。p53 是一种核磷酸蛋白转录因子，对于激活与细胞周期阻滞和应激诱导凋亡相关的基因表达至关重要。在神经退行性疾病中，p53 在神经胶质细胞中的表达显著增加，而小胶质细胞数量减少。在用嗜铬粒蛋白 A（100 nM）或β-淀粉样蛋白（25-35）（10 μM）激活后，小胶质细胞发生凋亡。此外，p53 表达增强，在暴露于激活剂后 4-6 小时达到峰值。p53 转录抑制剂 pifithrin-α（10 μM）显著降低了小胶质细胞中 p53 的表达，并显著调节了激活诱导的小胶质细胞凋亡的水平。氯化锂（5 mM）可以调节 p53 介导的途径，也降低了 p53 的表达和小胶质细胞的凋亡，提示糖原合酶激酶-3 发挥了作用。调节 p53 途径可调节小胶质细胞诱导型一氧化氮合酶的表达和肿瘤坏死因子-α的分泌。抑制 p53 介导的小胶质细胞凋亡可防止小胶质细胞神经毒性，这表明靶向小胶质细胞中 p53 介导的途径可能对阿尔茨海默病具有治疗益处。
