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.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Marcello E,Musardo S,Vandermeulen L,Pelucchi S,Gardoni F,Santo N,Antonucci F,Di Luca Mdoi
10.1007/s12035-019-1583-5subject
Has Abstractpub_date
2019-10-01 00:00:00pages
7136-7143issue
10eissn
0893-7648issn
1559-1182pii
10.1007/s12035-019-1583-5journal_volume
56pub_type
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