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

Elena Marcello1, Stefano Musardo2,3, Lina Vandermeulen2

  • 1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. elena.marcello@unimi.it.

Molecular Neurobiology
|April 17, 2019
PubMed

Insights

Alzheimer's disease (AD) oligomers disrupt synaptic plasticity by impairing ADAM10 internalization, a key enzyme in amyloid-β peptide regulation. This aberrant mechanism may downregulate amyloid-β generation while affecting structural plasticity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • A disintegrin and metalloproteinase 10 (ADAM10) is a synaptic enzyme regulating amyloid-β (Aβ) peptide formation in Alzheimer's disease (AD).
  • ADAM10 activity is modulated by synaptic plasticity, with long-term depression (LTD) promoting its synaptic localization and long-term potentiation (LTP) causing its internalization.
  • ADAM10 plays a role in spine shaping via cleavage of adhesion molecules.

Purpose of the Study:

  • To investigate the effect of amyloid-β oligomers on ADAM10 synaptic localization and internalization.
  • To elucidate the mechanism by which Aβ oligomers influence ADAM10 trafficking at the synapse.
  • To understand the interplay between Aβ oligomers, synaptic plasticity, and ADAM10 function in AD pathogenesis.

Main Methods:

  • In vitro exposure of hippocampal neuronal cultures to Aβ oligomers.
  • Analysis of ADAM10 synaptic localization and endocytosis.
  • Investigation of the role of neuronal activity and NMDA receptor activation.

Main Results:

  • Aβ oligomers induced increased ADAM10 synaptic localization, similar to LTD, but through impaired endocytosis, not enhanced delivery.
  • Aβ oligomers inhibited ADAM10 internalization in a manner dependent on neuronal activity and NMDA receptor activation.
  • These findings suggest Aβ oligomers trigger an aberrant synaptic plasticity mechanism.

Conclusions:

  • Aβ oligomers can downregulate Aβ generation by modulating ADAM10 synaptic availability via impaired internalization.
  • Altered ADAM10 activity may impact structural plasticity, contributing to AD pathogenesis.
  • This study reveals a complex relationship between synaptic activity and core AD mechanisms involving ADAM10.
Keywords:
ADAM10Alzheimer diseaseAmyloid-βSynaptic plasticity

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