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Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5

Marianne Renner1, Pascale N Lacor, Pauline T Velasco

  • 1Ecole Normale Supérieure, Institut de Biologie de l'Ecole Normale, Supérieure (IBENS), Inserm U1024, Paris France.

Neuron
|June 16, 2010
PubMed

Insights

Amyloid beta oligomers impair memory in Alzheimer's disease by binding to synapses. This study reveals how these amyloid beta (Abeta) oligomers cause synaptic failure by clustering glutamate receptors.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Soluble oligomers of amyloid beta (Abeta) are implicated in Alzheimer's disease-related memory deficits.
  • Abeta oligomers act as pathogenic ligands, disrupting synaptic function, morphology, and maintenance.

Purpose of the Study:

  • To investigate the early molecular events following Abeta oligomer binding to synapses in live hippocampal neurons.
  • To elucidate the mechanism by which Abeta oligomers induce synaptic failure.

Main Methods:

  • Single particle tracking of quantum dot-labeled Abeta oligomers and synaptic proteins.
  • Live imaging of hippocampal neurons.
  • Utilizing mGluR5 antagonists and artificial crosslinking for comparative analysis.

Main Results:

  • Abeta oligomers' diffusion is hindered upon synaptic accumulation.
  • Metabotropic glutamate receptor 5 (mGluR5) diffusion is reduced, leading to aberrant clustering.
  • mGluR5 clustering elevates intracellular calcium and causes synapse deterioration, a process preventable by mGluR5 antagonists.

Conclusions:

  • Abeta oligomers induce synaptic failure through the abnormal accumulation and overstabilization of mGluR5.
  • This provides a mechanistic and molecular basis for early synaptic dysfunction in Alzheimer's disease.
  • Targeting mGluR5 may offer a therapeutic strategy for Alzheimer's disease.

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