A disintegrin and metalloproteinase 10 (ADAM10) is a synaptic enzyme that has been previously shown to limit amyloid-β1-42 (Aβ1-42) peptide formation in Alzheimer's disease (AD). Furthermore, ADAM10 participates to spine shaping through the cleavage of adhesion molecules and its activity is under the control of synaptic plasticity events. In particular, long-term depression (LTD) promotes ADAM10 synaptic localization triggering its forward trafficking to the synapse, while long-term potentiation elicits ADAM10 internalization. Here, we show that a short-term in vitro exposure to Aβ1-42 oligomers, at a concentration capable of inducing synaptic depression and spine loss, triggers an increase in ADAM10 synaptic localization in hippocampal neuronal cultures. However, the Aβ1-42 oligomers-induced synaptic depression does not foster ADAM10 delivery to the synapse, as the physiological LTD, but impairs ADAM10 endocytosis. Moreover, Aβ1-42 oligomers-induced inhibition of ADAM10 internalization requires neuronal activity and the activation of the NMDA receptors. These data suggest that, at the synaptic level, Aβ1-42 oligomers trigger an aberrant plasticity mechanism according to which Aβ1-42 oligomers can downregulate Aβ generation through the modulation of ADAM10 synaptic availability. Moreover, the increased activity of ADAM10 towards its synaptic substrates could also affect the structural plasticity phenomena. Overall, these data shed new lights on the strict and complex relationship existing between synaptic activity and the primary mechanisms of AD pathogenesis.

Amyloid-β Oligomers Regulate ADAM10 Synaptic Localization Through Aberrant Plasticity Phenomena / E. Marcello, S. Musardo, L. Vandermeulen, S. Pelucchi, F. Gardoni, N. Santo, F. Antonucci, M. Di Luca. - In: MOLECULAR NEUROBIOLOGY. - ISSN 0893-7648. - (2019 Apr 13). [Epub ahead of print]

Amyloid-β Oligomers Regulate ADAM10 Synaptic Localization Through Aberrant Plasticity Phenomena

Marcello, Elena;Musardo, Stefano;Vandermeulen, Lina;Pelucchi, Silvia;Gardoni, Fabrizio;Santo, Nadia;Antonucci, Flavia;Di Luca, Monica
2019-04-13

Abstract

A disintegrin and metalloproteinase 10 (ADAM10) is a synaptic enzyme that has been previously shown to limit amyloid-β1-42 (Aβ1-42) peptide formation in Alzheimer's disease (AD). Furthermore, ADAM10 participates to spine shaping through the cleavage of adhesion molecules and its activity is under the control of synaptic plasticity events. In particular, long-term depression (LTD) promotes ADAM10 synaptic localization triggering its forward trafficking to the synapse, while long-term potentiation elicits ADAM10 internalization. Here, we show that a short-term in vitro exposure to Aβ1-42 oligomers, at a concentration capable of inducing synaptic depression and spine loss, triggers an increase in ADAM10 synaptic localization in hippocampal neuronal cultures. However, the Aβ1-42 oligomers-induced synaptic depression does not foster ADAM10 delivery to the synapse, as the physiological LTD, but impairs ADAM10 endocytosis. Moreover, Aβ1-42 oligomers-induced inhibition of ADAM10 internalization requires neuronal activity and the activation of the NMDA receptors. These data suggest that, at the synaptic level, Aβ1-42 oligomers trigger an aberrant plasticity mechanism according to which Aβ1-42 oligomers can downregulate Aβ generation through the modulation of ADAM10 synaptic availability. Moreover, the increased activity of ADAM10 towards its synaptic substrates could also affect the structural plasticity phenomena. Overall, these data shed new lights on the strict and complex relationship existing between synaptic activity and the primary mechanisms of AD pathogenesis.
ADAM10; Alzheimer disease; Amyloid-β; Synaptic plasticity
Settore BIO/14 - Farmacologia
Synaptic Dysfunction in Alzheimer Disease
Development of innovative tools for Alzheimer Disease therapy
Development of innovative tools for Alzheimer Disease therapy
Validating ADAM10 as therapeutic target for dementia
Meccanismi di patogenesi negli stadi precoci della malattia di Alzheimer: identificazione di target armacologici e biomarkers
Dipartimenti di Eccellenza 2018-2022 - Dipartimento di SCIENZE FARMACOLOGICHE E BIOMOLECOLARI
Medicina personalizzata per strategie innovative in malattie neuro-psichiatriche e vascolari (PerMedNet)
Fondo per il finanziamento delle attività base di ricerca - DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI
PIANO DI SOSTEGNO ALLA RICERCA 2015-2017 - LINEA 2 "DOTAZIONE ANNUALE PER ATTIVITA' ISTITUZIONALE"
MOLECULAR NEUROBIOLOGY
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/639925
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