Jimenez Sebastian, Baglietto-Vargas David, Caballero Cristina, Moreno-Gonzalez Ines, Torres Manuel, Sanchez-Varo Raquel, Ruano Diego, Vizuete Marisa, Gutierrez Antonia, Vitorica Javier
Department Bioquímica, Bromatologia, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
J Neurosci. 2008 Nov 5;28(45):11650-61. doi: 10.1523/JNEUROSCI.3024-08.2008.
Although the microglial activation is concomitant to the Alzheimer's disease, its precise role (neuroprotection vs neurodegeneration) has not yet been resolved. Here, we show the existence of an age-dependent phenotypic change of microglial activation in the hippocampus of PS1xAPP model, from an alternative activation state with Abeta phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF-alpha and related factors) at 18 months of age. This switch was coincident with high levels of soluble Abeta oligomers and a significant pyramidal neurodegeneration. In vitro assays, using astromicroglial cultures, demonstrated that oligomeric Abeta42 and soluble extracts from 18-month-old PS1xAPP hippocampus produced a potent TNF-alpha induction whereas monomeric Abeta42 and soluble extract from 6- or 18-month-old control and 6-month-old PS1xAPP hippocampi produced no stimulation. This stimulatory effect was avoided by immunodepletion using 6E10 or A11. In conclusion, our results show evidence of a switch in the activated microglia phenotype from alternative, at the beginning of Abeta pathology, to a classical at advanced stage of the disease in this model. This change was induced, at least in part, by the age-dependent accumulation of extracellular soluble Abeta oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.
尽管小胶质细胞激活与阿尔茨海默病同时发生，但其确切作用（神经保护与神经退行性变）尚未明确。在此，我们发现PS1xAPP模型海马中小胶质细胞激活存在年龄依赖性表型变化，从具有β淀粉样蛋白吞噬能力的替代激活状态（6个月时）转变为18个月龄时的经典细胞毒性表型（表达肿瘤坏死因子-α及相关因子）。这种转变与高水平的可溶性β淀粉样蛋白寡聚体以及显著的锥体神经元退行性变同时发生。使用星形胶质细胞-小胶质细胞共培养的体外实验表明，18个月龄PS1xAPP海马的寡聚体β淀粉样蛋白42和可溶性提取物可强力诱导肿瘤坏死因子-α，而单体β淀粉样蛋白42以及6个月龄和18个月龄对照海马及6个月龄PS1xAPP海马的可溶性提取物则无刺激作用。使用6E10或A11进行免疫去除可避免这种刺激作用。总之，我们的结果表明，在该模型中，激活的小胶质细胞表型在β淀粉样蛋白病变开始时从替代型转变为疾病晚期的经典型。这种变化至少部分是由细胞外可溶性β淀粉样蛋白寡聚体的年龄依赖性积累所诱导。最后，这些具有细胞毒性的激活小胶质细胞可能参与了阿尔茨海默病中观察到的神经元丢失。
