Deleterious Effects of Amyloid β Oligomers Acting as an Extracellular Scaffold for mGluR5

Marianne Renner, Pascale N. Lacor, Pauline T. Velasco, Jian Xu, Anis Contractor, William L. Klein, Antoine Triller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

313 Scopus citations

Abstract

Soluble oligomers of amyloid β (Aβ) play a role in the memory impairment characteristic of Alzheimer's disease. Acting as pathogenic ligands, Aβ oligomers bind to particular synapses and perturb their function, morphology, and maintenance. Events that occur shortly after oligomer binding have been investigated here in live hippocampal neurons by single particle tracking of quantum dot-labeled oligomers and synaptic proteins. Membrane-attached oligomers initially move freely, but their diffusion is hindered markedly upon accumulation at synapses. Concomitantly, individual metabotropic glutamate receptors (mGluR5) manifest strikingly reduced lateral diffusion as they become aberrantly clustered. This clustering of mGluR5 elevates intracellular calcium and causes synapse deterioration, responses prevented by an mGluR5 antagonist. As expected, clustering by artificial crosslinking also promotes synaptotoxicity. These results reveal a mechanism whereby Aβ oligomers induce the abnormal accumulation and overstabilization of a glutamate receptor, thus providing a mechanistic and molecular basis for Aβ oligomer-induced early synaptic failure.

Original languageEnglish (US)
Pages (from-to)739-754
Number of pages16
JournalNeuron
Volume66
Issue number5
DOIs
StatePublished - Jun 2010

Keywords

  • Cellbio
  • Molneuro
  • Signaling

ASJC Scopus subject areas

  • Neuroscience(all)

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