| First Author | Pannaccione A | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 31 | Pages | 10609-17 |
| PubMed ID | 22855810 | Mgi Jnum | J:186625 |
| Mgi Id | MGI:5432817 | Doi | 10.1523/JNEUROSCI.6429-11.2012 |
| Citation | Pannaccione A, et al. (2012) A New Concept: Abeta1-42 Generates a Hyperfunctional Proteolytic NCX3 Fragment That Delays Caspase-12 Activation and Neuronal Death. J Neurosci 32(31):10609-17 |
| abstractText | Although the amyloid-beta(1-42) (Abeta(1-42)) peptide involved in Alzheimer's disease is known to cause a dysregulation of intracellular Ca(2+) homeostasis, its molecular mechanisms still remain unclear. We report that the extracellular-dependent early increase (30 min) in intracellular calcium concentration ([Ca(2+)](i)), following Abeta(1-42) exposure, caused the activation of calpain that in turn elicited a cleavage of the Na(+)/Ca(2+) exchanger isoform NCX3. This cleavage generated a hyperfunctional form of the antiporter and increased NCX currents (I(NCX)) in the reverse mode of operation. Interestingly, this NCX3 calpain-dependent cleavage was essential for the Abeta(1-42)-dependent I(NCX) increase. Indeed, the calpain inhibitor calpeptin and the removal of the calpain-cleavage recognition sequence, via site-directed mutagenesis, abolished this effect. Moreover, the enhanced NCX3 activity was paralleled by an increased Ca(2+) content in the endoplasmic reticulum (ER) stores. Remarkably, the silencing in PC-12 cells or the knocking-out in mice of the ncx3 gene prevented the enhancement of both I(NCX) and Ca(2+) content in ER stores, suggesting that NCX3 was involved in the increase of ER Ca(2+) content stimulated by Abeta(1-42). By contrast, in the late phase (72 h), when the NCX3 proteolytic cleavage abruptly ceased, the occurrence of a parallel reduction in ER Ca(2+) content triggered ER stress, as revealed by caspase-12 activation. Concomitantly, the late increase in [Ca(2+)](i) coincided with neuronal death. Interestingly, NCX3 silencing caused an earlier activation of Abeta(1-42)-induced caspase-12. Indeed, in NCX3-silenced neurons, Abeta(1-42) exposure hastened caspase-dependent apoptosis, thus reinforcing neuronal cell death. These results suggest that Abeta(1-42), through Ca(2+)-dependent calpain activation, generates a hyperfunctional form of NCX3 that, by increasing Ca(2+) content into ER, delays caspase-12 activation and thus neuronal death. |
