Intraneuronal amyloid-β1-42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death
Article first published online: 20 JAN 2004
Journal of Neurochemistry
Volume 88, Issue 5, pages 1140–1150, March 2004
How to Cite
Pierrot, N., Ghisdal, P., Caumont, A.-S. and Octave, J.-N. (2004), Intraneuronal amyloid-β1-42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. Journal of Neurochemistry, 88: 1140–1150. doi: 10.1046/j.1471-4159.2003.02227.x
- Issue published online: 4 FEB 2004
- Article first published online: 20 JAN 2004
- Received September 1, 2003; revised manuscript received October 21, 2003; accepted October 28, 2003.
- Alzheimer's disease;
- amyloid peptide;
- amyloid precursor protein;
- neuronal death;
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of senile plaques which contain an amyloid core made of β-amyloid peptide (Aβ). Aβ is produced by the cleavage of the amyloid precursor protein (APP). Since impairment of neuronal calcium signalling has been causally implicated in ageing and AD, we have investigated the influence of an influx of extracellular calcium on the metabolism of human APP in rat cortical neurones. We report that a high cytosolic calcium concentration, induced by neuronal depolarization, inhibits the α-secretase cleavage of APP and triggers the accumulation of intraneuronal C-terminal fragments produced by the β-cleavage of the protein (CTFβ). Increase in cytosolic calcium concentration specifically induces the production of large amounts of intraneuronal Aβ1-42, which is inhibited by nimodipine, a specific antagonist of l-type calcium channels. Moreover, calcium release from endoplasmic reticulum is not sufficient to induce the production of intraneuronal Aβ, which requires influx of extracellular calcium mediated by the capacitative calcium entry mechanism. Therefore, a sustained high concentration of cytosolic calcium is needed to induce the production of intraneuronal Aβ1-42 from human APP. Our results show that this accumulation of intraneuronal Aβ1-42 induces neuronal death, which is prevented by a functional γ-secretase inhibitor.