INTEGRATION OF DIFFERENT PATHWAYS IN EARLY STAGE OF ALZHEIMER'S DISEASE PATHOGENESIS, FROM ACTIN REMODELLING TO AΒ FORMATION
Tesi di Dottorato
Data di Pubblicazione:
2017
Citazione:
INTEGRATION OF DIFFERENT PATHWAYS IN EARLY STAGE OF ALZHEIMER'S DISEASE PATHOGENESIS, FROM ACTIN REMODELLING TO AΒ FORMATION / S.c. Pelucchi ; tutor: M. Diluca ; coordinatore: A. Corsini. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2017 Jan 27. 29. ciclo, Anno Accademico 2016. [10.13130/pelucchi-silvia-cecilia_phd2017-01-27].
Abstract:
Alzheimer disease (AD) pathogenesis is the result of an interplay of crossing pathways, as amyloid cascade and synaptic failure. It has been shown that Aβ is liberated from the amyloid precursor protein (APP) by BACE and γ-secretase activity. Alternatively, APP is cleaved within Aβ domain by ADAM10, which prevents Aβ formation. ADAM10 is a synaptic protein and works as sheddase towards several neuronal cell adhesion molecules. Therefore, ADAM10 activity can regulate not only Aβ generation, but also the synaptic morphology and the degree of functional synaptic connectivity. ADAM10 represents a potential pharmacological target for AD because the upregulation of its activity limits Aβ formation and affects synaptic function. Since ADAM10 synaptic localization/activity is controlled by the interactions with different protein partners, we aimed at identifying novel protein partners of ADAM10. To this, we performed a yeast two-hybrid screening, using ADAM10 C-terminal tail as a bait. We took advantage of several biochemical and imaging technique to analyze the role of such interaction.
The results revealed the cyclase-associated protein 2 (CAP2) as a new ADAM10 binding partner. CAP2 is a regulator of actin dynamics and, thereby, of spines morphology, and could be involved in the modulation of ADAM10 synaptic localization/activity. Here we confirmed ADAM10/CAP2 interaction and we identified the domains responsible for the association. Moreover, we defined the region of CAP2 involved in actin binding and we analyzed the effect of such domain on ADAM10 synaptic localization.
CAP2 can represent the crossing point between different aspects of AD pathogenesis, such as the amyloid cascade and actin-dependent spines shaping, thus taking part in a new cellular mechanism underlying synaptic dysfunction in AD.
Tipologia IRIS:
Tesi di dottorato
Elenco autori:
S.C. Pelucchi
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