Ca2+‐dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β‐treated astrocytes and in a model of Alzheimer's disease

Summary Neurotoxic effects of amyloid β peptides are mediated through deregulation of intracellular C a 2+ homeostasis and signaling, but relatively little is known about amyloid β modulation of C a 2+ homeostasis and its pathological influence on glia. Here, we found that amyloid β oligomers caused a cytoplasmic C a 2+ increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER C a 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 eIF 2α phosphorylation and overexpression of chaperone GRP 78. These effects were decreased by ryanodine and 2 APB , inhibitors of ryanodine receptors and I ns P 3 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 GRP 78 in astrocytes of the hippocampal dentate gyrus. These data were validated in a triple‐transgenic mouse model of A lzheimer's disease ( AD ). Overexpression of GFAP and GRP 78 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.