A hyperfunctional NCX3-proteolytic fragment generated by Abeta1-42 delays caspase-12 activation and neuronal death in mice

D'Avanzo, Carla (2011) A hyperfunctional NCX3-proteolytic fragment generated by Abeta1-42 delays caspase-12 activation and neuronal death in mice. [Tesi di dottorato] (Inedito)

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Abstract

Abeta1-42, the peptide involved in the pathogenesis of Alzheimer’s disease, causes a dysregulation of intracellular Ca2+ homeostasis. However, all the mechanisms involved in this process remain unknown. Here, we reported that A1-42 induced an increase in NCX currents (INCX) in the reverse mode of operation that was completely prevented by silencing or knocking-out the ncx3 gene. Moreover, a calpain-dependent cleavage of NCX3 was essential for the Abeta1-42-dependent INCX increase. Indeed, the removal of the calpain recognition-site abolished the Abeta1-42-stimulatory effect on INCX. Consistently, the N-terminal proteolytic fragment of NCX3 generated INCX comparable to those recorded after Abeta1-42 exposure. On the other hand, Abeta1-42 exposure increased Ca2+ refilling into endoplasmic reticulum (ER), an event that was prevented in neurons silenced or knocked-out for NCX3. This latter finding suggested that NCX3 was involved in ER Ca2+-refilling stimulated by Abeta1-42. Finally, NCX3 silencing caused an earlier activation of Abeta1-42-induced caspase-12. Indeed, in NCX3 silenced neurons, Abeta1-42 exposure hastened caspase-dependent apoptosis, thus reinforcing neuronal cell death. Altogether, these results suggested that the NCX3 hyperfunctional proteolytic fragment, produced by Abeta1-42-induced calpain activation, contributed to neuronal Ca2+-refilling into ER. This event exerted a neuroprotective effect during Abeta1-42 insult by delaying caspase-12 activation, apoptosis, and neuronal death.

Tipologia di documento:Tesi di dottorato
Parole chiave:NCX3, Abeta1-42
Settori scientifico-disciplinari MIUR:Area 05 Scienze biologiche > BIO/14 FARMACOLOGIA
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Annunziato, Luciolannunzi@unina.it
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Pannaccione, Annapannacio@unina.it
Stato del full text:Accessibile
Data:30 Novembre 2011
Numero di pagine:76
Istituzione:Università di Napoli Federico II
Dipartimento o Struttura:Neuroscienze
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina molecolare
Denominazione del dottorato:Neuroscienze
Ciclo di dottorato:24
Numero di sistema:8751
Depositato il:07 Dicembre 2011 11:49
Ultima modifica:23 Aprile 2012 11:50

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