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 β (Aβ) is an initiator of a cascade of events eventually leading to neurodegeneration. Recently, we reported that Aβ deranged Ca(2+) homeostasis specifically in hippocampal astrocytes by targeting key elements of Ca(2+) signaling, such as mGluR5 and IP3 R1. In the present study, we dissect a cascade of signaling events by which Aβ deregulates glial Ca(2+) : (i) 100 nM Aβ 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 Aβ 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 Aβ plaques and co-localizes with nuclear accumulation of the p65 NF-kB subunit and increased staining of CaNAα. Taken together our data suggest that nanomolar [Aβ] deregulates Ca(2+) homeostasis via CaN and its downstream target NF-kB, possibly via the cross-talk of Bcl10 in hippocampal astrocytes.