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:
AutoreEmail
D'Avanzo, Carlacarla.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:
nomeemail
Annunziato, Luciolannunzi@unina.it
Tutor:
nomeemail
Pannaccione, Annapannacio@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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