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 Ca²⁺ homeostasis specifically in hippocampal astrocytes by targeting key elements of Ca²⁺ signaling, such as mGluR5 and IP₃R1. In the present glial Ca²⁺: (i) 100 nM Aβ leads to an increase in cytosolic calcium after 4-6 study, we dissect a cascade of signaling events by which Aβ deregulates 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 Ca²⁺ homeostasis via CaN and its downstream target NF-kB, possibly via the cross-talk of Bcl10 in hippocampal astrocytes