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 language | English (US) |
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Pages (from-to) | 739-754 |
Number of pages | 16 |
Journal | Neuron |
Volume | 66 |
Issue number | 5 |
DOIs | |
State | Published - Jun 2010 |
Funding
P.N.L., P.T.V, and W.L.K were supported by Alzheimer's Association IIRG-06-26989, American Health Association A2006-092, and National Institutes of Health RO1AG029460, and partially by the Nanoscale Science and Engineering Initiative of the National Science Foundation (NSF) under NSF Award Number EEC-06475560. Thanks to C. Mirkin for attributing to P.N.L an international travel grant under the NSF Award mentioned above. The authors thank A. Wadhwani and R. Sureka for their help with the biochemistry experiments. M.R. was supported by the Agence Nationale de la Recherche grant Neur-043-02. This research was partially funded by the Fondation pour la Recherche Médicale. We thank L. Fagni (Montpellier, France) for kindly provide us with the construct of mGluR5-Venus. W.L.K. is cofounder of Acumen Pharmaceuticals, licensed by Northwestern to develop Alzheimer's therapeutics and diagnostics that target ADDLs.
Keywords
- Cellbio
- Molneuro
- Signaling
ASJC Scopus subject areas
- General Neuroscience