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The β‐amyloid precursor protein controls a store‐operated Ca 2+ entry in cortical neurons
Author(s) -
Bouron Alexandre,
Mbebi Corinne,
Loeffler JeanPhilippe,
De Waard Michel
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2004.03680.x
Subject(s) - intracellular , amyloid precursor protein , extracellular , microbiology and biotechnology , neurite , chemistry , phospholipase d , biology , biochemistry , medicine , signal transduction , alzheimer's disease , disease , in vitro
A polyclonal antibody (APP‐Ab) raised against the extracellular domain of the beta‐amyloid precursor protein (APP) triggers a marked neuronal cell death preceded by activation of Ca 2+ ‐dependent enzymes, neurite degeneration, oxidative stress and nuclear condensation [Mbebi et al. (2002) J. Biol. Chem. , 277 , 20979–20990]. We have investigated whether activation of APP by this antibody could promote cell death through cellular Ca 2+ homeostasis alteration. We carried out time‐lapse recordings of intracellular Ca 2+ signals in cultured mice cortical neurons by means of a scanning confocal microscope. When applied in the presence of 2 m m external Ca 2+ , APP‐Ab elicited a long‐lasting elevation of the intracellular concentration of Ca 2+ ([Ca 2+ ] i ). Experiments performed in the absence of external Ca 2+ showed that APP‐Ab triggers the release of Ca 2+ from intracellular stores. The re‐admission of external Ca 2+ provides an additional rise of Ca 2+ most likely through store‐operated channels. A pretreatment of the cells with pertussis toxin, to inhibit the activity of G i /G o proteins, or with the phospholipase C inhibitor, 3‐nitrocoumarin, prevented both the APP‐dependent elevation of Ca 2+ as well as the APP‐Ab‐mediated cell death. Similarly, the store‐operated channel inhibitors, 2‐APB or SKF‐96365 block both the APP‐Ab‐dependent Ca 2+ entry and the APP‐Ab‐mediated cell death. Altogether, our data provide functional evidence that APP can perturb intracellular Ca 2+ homeostasis by emptying intracellular Ca 2+ stores and triggering Ca 2+ entry through store‐operated channels. In response to APP activation, the long‐lasting elevation of [Ca 2+ ] i due to an entry of Ca 2+ via store‐operated channels appears as a major event that leads to neuronal cell death.