Ca2[sup]+-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid [beta]-treated astrocytes and in a model of Alzheimer's disease
Alberdi, Elena ...
Neurotoxic effects of amyloid beta peptides are mediated through deregulation of intracellular Ca[sup]2+ homeostasis and signaling, but relatively little is known about amyloid beta modulation of ...Ca[sup]2+ homeostasis and its pathological influence on glia. Here, we found that amyloid [beta] oligomers caused a cytoplasmic Ca(2+) increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER Ca[sup]2+ release. Furthermore, amyloid beta peptides triggered increased expression of glial fibrillary acidic protein (GFAP), as well as oxidative and ER stress, as indicated by eIF2[alpha] 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 beta 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 beta 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 beta oligomers disrupt ER Ca[sup]2+homeostasis, which induces ER stress that leads to astrogliosis; this mechanism may be relevant to AD pathophysiology.
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