Facultad de Farmacia, Departamento de Bioquímica y Biología Molecular, Universidad de Sevilla, Spain.
Cell Death Differ. 2011 Nov;18(11):1679-91. doi: 10.1038/cdd.2011.107. Epub 2011 Aug 12.
Activation of microglia and inflammation-mediated neurotoxicity are suggested to have key roles in the pathogenesis of several neurodegenerative disorders. We recently published an article in Nature revealing an unexpected role for executioner caspases in the microglia activation process. We showed that caspases 8 and 3/7, commonly known to have executioner roles for apoptosis, can promote microglia activation in the absence of death. We found these caspases to be activated in microglia of PD and AD subjects. Inhibition of this signaling pathway hindered microglia activation and importantly reduced neurotoxicity in cell and animal models of disease. Here we review evidence suggesting that microglia can have a key role in the pathology of neurodegenerative disorders. We discuss possible underlying mechanisms regulating their activation and neurotoxic effect. We focus on the provocative hypothesis that caspase inhibition can be neuroprotective by targeting the microglia rather than the neurons themselves.
小胶质细胞的激活和炎症介导的神经毒性被认为在几种神经退行性疾病的发病机制中起关键作用。我们最近在《自然》杂志上发表了一篇文章，揭示了细胞凋亡中的执行者半胱天冬酶在小胶质细胞激活过程中的一个意外作用。我们表明，细胞凋亡中通常具有执行者作用的半胱天冬酶 8 和 3/7 可以在没有死亡的情况下促进小胶质细胞的激活。我们发现这些半胱天冬酶在 PD 和 AD 患者的小胶质细胞中被激活。抑制这条信号通路会阻碍小胶质细胞的激活，并在疾病的细胞和动物模型中重要地减少神经毒性。在这里，我们综述了小胶质细胞可能在神经退行性疾病的病理中起关键作用的证据。我们讨论了调节其激活和神经毒性作用的可能潜在机制。我们特别关注这样一个有争议的假设，即通过针对小胶质细胞而不是神经元本身来抑制半胱天冬酶可以起到神经保护作用。
