title: Amyloid beta deregulates astroglial mGluR5-mediated calcium signaling via calcineurin and Nf-kB.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro,", Novara, Italy.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lim
authors.forename: Anand
authors.initials: A
authors.lastname: Iyer
authors.forename: Virginia
authors.initials: V
authors.lastname: Ronco
authors.forename: Ambra A
authors.initials: AA
authors.lastname: Grolla
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001896:Boron Compounds / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D001896:Boron Compounds; D002614:Chelating Agents; D004791:Enzyme Inhibitors; C578937:Grm5 protein, rat; D016328:NF-kappa B; D009363:Neoplasm Proteins; D029543:Nucleocytoplasmic Transport Proteins; D010446:Peptide Fragments; D064529:Receptor, Metabotropic Glutamate 5; C075222:amyloid beta-protein (1-42); C063447:p65 oncofetal mRNA transport protein, rat; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C109986:2-aminoethoxydiphenyl borate; D019703:Calcineurin; D002118:Calcium