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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Tipologia del documento:	Tesi di dottorato
Lingua:	English
Titolo:	A hyperfunctional NCX3-proteolytic fragment generated by Abeta1-42 delays caspase-12 activation and neuronal death in mice
Autori:	Autore Email D'Avanzo, Carla carla.davanzo@unina.it
Data:	30 Novembre 2011
Numero di pagine:	76
Istituzione:	Università degli Studi di Napoli Federico II
Dipartimento:	Neuroscienze
Scuola di dottorato:	Medicina molecolare
Dottorato:	Neuroscienze
Ciclo di dottorato:	24
Coordinatore del Corso di dottorato:	nome email Annunziato, Lucio lannunzi@unina.it
Tutor:	nome email Pannaccione, Anna pannacio@unina.it
Data:	30 Novembre 2011
Numero di pagine:	76
Parole chiave:	NCX3, Abeta1-42
Settori scientifico-disciplinari del MIUR:	Area 05 - Scienze biologiche > BIO/14 - Farmacologia
Depositato il:	07 Dic 2011 10:49
Ultima modifica:	30 Apr 2014 19:48
URI:	http://www.fedoa.unina.it/id/eprint/8751
DOI:	10.6092/UNINA/FEDOA/8751

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.

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