MOLECULAR ASPECTS OF ALZHEIMER'S DISEASE PATHOGENESIS: FROM LOCAL SPINE TRAFFICKING TO LONG DISTANCE SPINE TO NUCLEUS SIGNALLING.'TOWARDS NEW THERAPEUTICS INTERVENTION'
Tesi di Dottorato
Data di Pubblicazione:
2016
Citazione:
MOLECULAR ASPECTS OF ALZHEIMER'S DISEASE PATHOGENESIS: FROM LOCAL SPINE TRAFFICKING TO LONG DISTANCE SPINE TO NUCLEUS SIGNALLING.'TOWARDS NEW THERAPEUTICS INTERVENTION' / S. Musardo ; tutor: M. Di Luca ; coordinatore: A. Corsini. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2016 Jan 11. 28. ciclo, Anno Accademico 2015. [10.13130/s-musardo_phd2016-01-11].
Abstract:
The molecular pathogenesis of Alzheimer’s disease (AD) is still controversial, although genetic and cell biology findings indicate accumulation of Aβ, especially in soluble oligomeric conformation, as the driving force of synaptic dysfunction with concomitant activation of complex cascade of molecular events leading to dementia. In the last few years, several studies aimed at understanding how Aβ accumulation and assembly compromise synaptic structure and function of excitatory synapses. In this study, we evaluated how Aβ can affect the local and the long-distance trafficking, since the alteration of these mechanisms could represent a key determinant for synaptic dysfunction. We focused the attention on ADAM10, which activity prevents Aβ production. Notably the regulation of ADAM10 synaptic localization is neuronal activity-dependent, in particular LTP decrease, while LTD foster ADAM10 surface expression. Here we found that Aβ42 (500nM, 30 min) exposure results in an increase of ADAM10 synaptic availability. In particular, Aβ42 treatment leads to a decrease in the association between ADAM10 and AP2 complex, suggesting that the augment in ADAM10 synaptic localization is due to a decrease of the endocytosis. Interestingly, this mechanism is completely lost in the context of AD, suggesting that the increase in ADAM10 endocytosis, and thus the reduction of its activity towards APP, could be a synaptic mechanism of AD pathogenesis. In light of this consideration, we developed CPPs able to interfere with ADAM10 clathrin-mediated endocytosis and to restore the unbalance between exo- and endocytosis. This tool can be considered a potential disease-modifying strategy capable of modifying the progression of the disease and rescuing the pathological phenotype. Afterwards we describe a novel synapse-to-nucleus signaling pathway, involving the RNF10 protein, that specifically links activation of synaptic GluN2A-containing NMDARs to nuclear gene expression. In physiological conditions, RNF10 dissociates from the NMDAR complex in an activity-dependent manner and we provide compelling evidence for importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. These findings suggest that synaptonuclear trafficking of RNF10 is involved in the control of gene expression, which is necessary for synaptic plasticity in hippocampal neurons. Here we demonstrated that Aβ can affect RNF10 long-distance trafficking. In particular, during acute exposure, Aβ induces RNF10 translocation while in a chronic AD pathological context we found a reduction of the translocation, suggesting that RNF10 could be involved in AD pathogenesis.
Tipologia IRIS:
Tesi di dottorato
Keywords:
Alzheimer's disease; ADAM10; RNF10; local trafficking; synapse to nucleus trafficking; synaptic dysfunction
Elenco autori:
S. Musardo
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