Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5.
Soluble oligomers of amyloid beta (Abeta) play a role in the memory impairment characteristic of Alzheimer's disease. Acting as pathogenic ligands, Abeta 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 Abeta oligomers induce the abnormal accumulation and overstabilization of a glutamate receptor, thus providing a mechanistic and molecular basis for Abeta oligomer-induced early synaptic failure.
Renner
Marianne
M
Ecole Normale Supérieure, Institut de Biologie de l'Ecole Normale, Supérieure (IBENS), Inserm U1024, Paris France.
Lacor
Pascale N
PN
Velasco
Pauline T
PT
Xu
Jian
J
Contractor
Anis
A
Klein
William L
WL
Triller
Antoine
A
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D055550:Protein Stability; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism* / Q000502:physiology; D013569:Synapses / Q000378:metabolism / Q000473:pathology
D016229:Amyloid beta-Peptides; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate