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- Title
Theβ-amyloid precursor protein controls a store-operated Ca<sup>2+</sup> entry in cortical neurons.
- Authors
Bouron, Alexandre; Mbebi, Corinne; Loeffler, Jean‐Philippe; De Waard, Michel
- Abstract
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 Ca2+-dependent enzymes, neurite degeneration, oxidative stress and nuclear condensation[Mbebiet al.(2002)J. Biol. Chem.,277, 20979–20990]. We have investigated whether activation of APP by this antibody could promote cell death through cellular Ca2+ homeostasis alteration. We carried out time-lapse recordings of intracellular Ca2+ signals in cultured mice cortical neurons by means of a scanning confocal microscope. When applied in the presence of 2 mmexternal Ca2+, APP-Ab elicited a long-lasting elevation of the intracellular concentration of Ca2+ ([Ca2+]i). Experiments performed in the absence of external Ca2+ showed that APP-Ab triggers the release of Ca2+ from intracellular stores. The re-admission of external Ca2+ provides an additional rise of Ca2+ most likely through store-operated channels. A pretreatment of the cells with pertussis toxin, to inhibit the activity of Gi/Go proteins, or with the phospholipase C inhibitor, 3-nitrocoumarin, prevented both the APP-dependent elevation of Ca2+ 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 Ca2+ entry and the APP-Ab-mediated cell death. Altogether, our data provide functional evidence that APP can perturb intracellular Ca2+ homeostasis by emptying intracellular Ca2+ stores and triggering Ca2+ entry through store-operated channels. In response to APP activation, the long-lasting elevation of[Ca2+]i due to an entry of Ca2+ via store-operated channels appears as a major event that leads to neuronal cell death.
- Subjects
AMYLOID; PROTEIN precursors; CALCIUM ions; NEURONS; CELL death; HOMEOSTASIS
- Publication
European Journal of Neuroscience, 2004, Vol 20, Issue 8, p2071
- ISSN
0953-816X
- Publication type
Article
- DOI
10.1111/j.1460-9568.2004.03680.x