Inflammatory Response in the Hippocampus of PS1M146L/APP751SL Mouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic
Inflammatory Response in the Hippocampus of PS1M146L/APP751SL Mouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic
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DOI：
10.1523/jneurosci.3024-08.2008
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发表时间：
2008-11-05
影响因子：
5.3
通讯作者：
Vitorica, Javier
中科院分区：
文献类型：
--
作者：
Jimenez, Sebastian;Baglietto-Vargas, David;Vitorica, Javier
虽然小胶质细胞的激活是伴随着阿尔茨海默病，其确切的作用（神经保护与神经变性）尚未得到解决。在这里，我们显示了PS1 xAPP模型海马中小胶质细胞活化的年龄依赖性表型变化的存在，从具有A β吞噬能力的替代活化状态（6个月时）到18个月龄时的经典细胞毒性表型（表达TNF-α和相关因子）。这种转换与高水平的可溶性A β寡聚体和显著的锥体神经变性一致。使用星形小胶质细胞培养物的体外试验表明，18个月大的PS1 xAPP海马体的寡聚A β 42和可溶性提取物产生了有效的TNF-α诱导，而6个月或18个月大的对照和6个月大的PS1 xAPP海马体的单体A β 42和可溶性提取物没有产生刺激。通过使用6 E10或A11的免疫耗竭避免了这种刺激作用。总之，我们的研究结果表明，在该模型中，活化的小胶质细胞表型从A β病理学开始时的替代表型转换为疾病晚期的经典表型。这种变化至少部分是由细胞外可溶性A β寡聚体的年龄依赖性积累引起的。最后，这些细胞毒性激活的小胶质细胞可以参与AD中观察到的神经元丢失。
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 A beta 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 A beta oligomers and a significant pyramidal neurodegeneration. In vitro assays, using astromicroglial cultures, demonstrated that oligomeric A beta 42 and soluble extracts from 18-month-old PS1xAPP hippocampus produced a potent TNF-alpha induction whereas monomeric A beta 42 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 A beta 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 A beta oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.