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Aging Cell. 2013 Apr;12(2):292-302. doi: 10.1111/acel.12054. Epub 2013 Feb 28.

Ca(2+) -dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease.

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Departamento de Neurociencias, Achucarro Basque Center for Neuroscience, Universidad del País Vasco (UPV/EHU), 48940, Leioa, Spain.


Neurotoxic effects of amyloid β peptides are mediated through deregulation of intracellular Ca(2+) homeostasis and signaling, but relatively little is known about amyloid β modulation of Ca(2+) homeostasis and its pathological influence on glia. Here, we found that amyloid β oligomers caused a cytoplasmic Ca(2+) increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER Ca(2+) release. Furthermore, amyloid β peptides triggered increased expression of glial fibrillary acidic protein (GFAP), as well as oxidative and ER stress, as indicated by eIF2α 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 β 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 β 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 β oligomers disrupt ER Ca(2+) homeostasis, which induces ER stress that leads to astrogliosis; this mechanism may be relevant to AD pathophysiology.

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