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

SummarySoluble 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.

► Aβ oligomers bind, diffuse, and subsequently form clusters at the neuronal plasma membrane ► mGluR5 receptors are involved in the binding of Aβ oligomers to the plasma membrane ► The clustering of Aβ oligomers alters the distribution and mobility mGluR5 receptors ► mGluR5 receptor redistribution promotes an intracellular Ca2+ increase and a loss of NMDAR