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

Glia. 2013 Jul;61(7):1134-45. doi: 10.1002/glia.22502. Epub 2013 Apr 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects*
  • B-Cell CLL-Lymphoma 10 Protein
  • Boron Compounds / pharmacology
  • Calcineurin / metabolism*
  • Calcium / metabolism
  • Calcium Signaling / drug effects*
  • Calcium Signaling / physiology
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Male
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / metabolism
  • Nucleocytoplasmic Transport Proteins / metabolism
  • Peptide Fragments / pharmacology*
  • Rats
  • Receptor, Metabotropic Glutamate 5 / genetics
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Up-Regulation / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • Boron Compounds
  • Chelating Agents
  • Enzyme Inhibitors
  • Grm5 protein, rat
  • NF-kappa B
  • Neoplasm Proteins
  • Nucleocytoplasmic Transport Proteins
  • Peptide Fragments
  • Receptor, Metabotropic Glutamate 5
  • amyloid beta-protein (1-42)
  • p65 oncofetal mRNA transport protein, rat
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • Egtazic Acid
  • 2-aminoethoxydiphenyl borate
  • Calcineurin
  • Calcium