Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid -treated astrocytes and in a model of Alzheimer's disease
Ca2+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid -treated astrocytes and in a model of Alzheimer's disease
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DOI：
10.1111/acel.12054
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发表时间：
2013-04-01
期刊：
影响因子：
7.8
通讯作者：
Matute, Carlos
中科院分区：
文献类型：
--
作者：
Alberdi, Elena;Wyssenbach, Ane;Matute, Carlos
淀粉样肽的神经毒性作用是通过胞内Ca 2+稳态和信号转导的失调介导的，但关于淀粉样蛋白对Ca 2+稳态的调节及其对胶质细胞的病理影响知之甚少。在这里，我们发现，淀粉样蛋白低聚物引起的细胞质Ca 2+的增加，在培养的星形胶质细胞，这是减少PLC和ER的Ca 2+释放的抑制剂。此外，淀粉样肽触发了胶质细胞酸性蛋白（GFAP）的表达增加，以及氧化和ER应激，如eIF 2磷酸化和伴侣GRP 78的过表达所示。这些影响降低了Ryanodine和2APB，Ryanodine受体和InsP 3受体的抑制剂，分别在原代培养的星形胶质细胞和海马和内嗅皮质的器官型培养。重要的是，侧脑室注射淀粉样蛋白寡聚体触发了海马齿状回星形胶质细胞中GFAP和GRP 78的过度表达。这些数据在阿尔茨海默病（AD）的三重转基因小鼠模型中得到验证。海马星形胶质细胞中GFAP和GRP 78的过表达与12月龄小鼠中的淀粉样蛋白寡聚体负荷相关，表明该参数驱动体内星形胶质细胞ER应激和星形胶质细胞增生。总之，这些结果提供了证据表明淀粉样蛋白低聚物破坏ER Ca 2+稳态，从而诱导ER应激，导致星形胶质细胞增生;这种机制可能与AD病理生理学相关。
Neurotoxic effects of amyloid peptides are mediated through deregulation of intracellular Ca2+ homeostasis and signaling, but relatively little is known about amyloid modulation of Ca2+ homeostasis and its pathological influence on glia. Here, we found that amyloid oligomers caused a cytoplasmic Ca2+ increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER Ca2+ release. Furthermore, amyloid peptides triggered increased expression of glial fibrillary acidic protein (GFAP), as well as oxidative and ER stress, as indicated by eIF2 phosphorylation and overexpression of chaperone GRP78. These effects were decreased by ryanodine and 2APB, inhibitors of ryanodine receptors and InsP3 receptors, respectively, in both primary cultured astrocytes and organotypic cultures of hippocampus and entorhinal cortex. Importantly, intracerebroventricular injection of amyloid oligomers triggered overexpression of GFAP and GRP78 in astrocytes of the hippocampal dentate gyrus. These data were validated in a triple-transgenic mouse model of Alzheimer's disease (AD). Overexpression of GFAP and GRP78 in the hippocampal astrocytes correlated with the amyloid oligomer load in 12-month-old mice, suggesting that this parameter drives astrocytic ER stress and astrogliosis in vivo. Together, these results provide evidence that amyloid oligomers disrupt ER Ca2+ homeostasis, which induces ER stress that leads to astrogliosis; this mechanism may be relevant to AD pathophysiology.