Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB

The amyloid hypothesis of Alzheimer's disease (AD) suggests that soluble amyloid (A) is an initiator of a cascade of events eventually leading to neurodegeneration. Recently, we reported that A deranged Ca2+ homeostasis specifically in hippocampal astrocytes by targeting key elements of Ca2+ signaling, such as mGluR5 and IP3R1. In the present study, we dissect a cascade of signaling events by which A deregulates glial Ca2+: (i) 100 nM A leads to an increase in cytosolic calcium after 4-6 h of treatment; (ii) mGluR5 is increased after 24 h of treatment; (iii) this increase is blocked by inhibitors of calcineurin (CaN) and NF-kB. Furthermore, we show that A treatment of glial cells leads to de-phosphorylation of Bcl10 and an increased CaN-Bcl10 interaction. Last, mGluR5 staining is augmented in hippocampal astrocytes of AD patients in proximity of A plaques and co-localizes with nuclear accumulation of the p65 NF-kB subunit and increased staining of CaNA. Taken together our data suggest that nanomolar [A] deregulates Ca2+ homeostasis via CaN and its downstream target NF-kB, possibly via the cross-talk of Bcl10 in hippocampal astrocytes.