Kingham P J, Pocock J M
Department of Neurochemistry, Institute of Neurology, University College London, London, UK.
J Neurochem. 2001 Mar;76(5):1475-84. doi: 10.1046/j.1471-4159.2001.00146.x.
Activated microglia release a number of substances that can influence neuronal signalling and survival. Here we report that microglia stimulated with the peptide chromogranin A (CGA), secreted the cysteine protease, cathepsin B. Conditioned medium from CGA exposed microglia was neurotoxic to the HT22 hippocampal cell line and to primary cultures of cerebellar granule neurones. In both neuronal cell types, the neurotoxicity could be significantly attenuated with z-FA-fmk or by depletion of microglial conditioned medium with cathepsin B antibody. Conditioned medium from activated microglia or cathepsin B alone induced neuronal apoptosis and caspase 3 activation. Our data indicate that CGA-activated microglia can trigger neuronal apoptosis and that this may be mediated through the secretion of cathepsin B. Since cathepsins may also play a role in the amyloidogenic processing of amyloid precursor protein, these results may have significance for tissue damage and neuronal loss in the neuropathology of Alzheimer's disease.
活化的小胶质细胞会释放多种能够影响神经元信号传导和存活的物质。在此我们报告，用嗜铬粒蛋白A（CGA）肽刺激的小胶质细胞会分泌半胱氨酸蛋白酶组织蛋白酶B。来自暴露于CGA的小胶质细胞的条件培养基对HT22海马细胞系和小脑颗粒神经元原代培养物具有神经毒性。在这两种神经元细胞类型中，z-FA-fmk或用组织蛋白酶B抗体耗尽小胶质细胞条件培养基可显著减弱神经毒性。来自活化小胶质细胞的条件培养基或单独的组织蛋白酶B可诱导神经元凋亡和半胱天冬酶3激活。我们的数据表明，CGA活化的小胶质细胞可触发神经元凋亡，这可能是通过组织蛋白酶B的分泌介导的。由于组织蛋白酶也可能在淀粉样前体蛋白的淀粉样生成加工中起作用，这些结果可能对阿尔茨海默病神经病理学中的组织损伤和神经元丢失具有重要意义。
