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Amyloid beta deregulates astroglial mGluR5‐mediated calcium signaling via calcineurin and Nf‐kB
Author(s) -
Lim Dmitry,
Iyer Anand,
Ronco Virginia,
Grolla Ambra A.,
Caico Pier Luigi,
Aronica Eleonora,
Genazzani Armando A.
Publication year - 2013
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22502
Subject(s) - neurodegeneration , biology , calcineurin , microbiology and biotechnology , amyloid beta , hippocampal formation , neuroscience , biochemistry , medicine , peptide , disease , transplantation
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 IP 3 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.