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Florean, Cristina (2009) Messa a punto di un nuovo metodo biomolecolare per la misura dell’attività gamma-secretasica in cellule viventi. [Ph.D. thesis]

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Abstract (english)

gamma-Secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP), Notch and other cellular substrates and is considered a prime pharmacological target in the development of therapeutics for Alzheimer's disease (AD) and cancer. We describe here an efficient, new, simple, sensitive and rapid assay to quantify gamma-secretase activity in living cells by flow cytometry using membrane-bound fluorescent probes, APP-GFP or C99-GFP,and Notch-De GFP as substrates for gamma-secretase. By applying two well-known gamma-secretase inhibitors (DAPT and L-685,458), we validated our assay showing that the positional GFP-based probes for gamma-secretase activity behave properly when expressed in different cell lines. Moreover, by co-expression of different familial AD-linked mutated forms of presenilin--the key component of the gamma-secretase complex--in cells devoid of any endogenous gamma-secretase, our method allowed us to evaluate in situ the contribution of different presenilin variants to the modulation of the enzyme.

Abstract (italian)

La gamma secretasi media la proteolisi in un sito intramembrana della proteina precursore dell'amiloide (APP), di Notch e di altri substrati cellulari, ed è considerata un target farmacologico primario nella ricerca per la terapia della malattia di Alzheimer e recentemente per il cancro. In questo lavoro è descritto un nuovo, semplice e rapido test per misurare l'attività di questo enzima in cellule viventi usando delle sonde fluorescenti membranose, APP-GFP, C99-GFP e NotchDeGFP, come substrati della gamma secretasi. Abbiamo convalidato il test applicando degli inibitori dell'enzima noti (DAPT and L-685,458), mostrando che le nostre sonde posizionali funzionano bene espresse in diverse linee cellulari. Inoltre, coesprimendo diverse forme doi presenilina (il centro catalitico della secretasi) è stato valutato il ruolo delle varianti di presenilina nella modulazione dell'enzima.

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EPrint type:Ph.D. thesis
Tutor:Pizzo, Paola and De Giorgi, Francesca
Ph.D. course:Ciclo 21 > Scuole per il 21simo ciclo > BIOSCIENZE > NEUROBIOLOGIA
Data di deposito della tesi:28 January 2009
Anno di Pubblicazione:2009
Key Words:Alzheimer, gamma secretasi, Presenilina, APP, Notch, citometria di flusso.
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/15 Biologia farmaceutica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Biomediche Sperimentali
Codice ID:1563
Depositato il:28 Jan 2009
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