Sci. Signal., 15 June 2010
Neurodegeneration Toxic Clusters
Science Signaling, AAAS, Washington, DC 20005, USA
Oligomerization of the β-amyloid (Aβ) peptide is thought to drive the pathogenesis of Alzheimers disease. One mechanism by which Aβ oligomers can cause neuronal dysfunction is through changes in calcium signaling. Renner et al. incubated biotinylated Aβ oligomers (b-Aβo) with cultured hippocampal neurons and found that b-Aβo colocalized with Homer1b/c, a protein found in excitatory synapses, but not with gephyrin, a protein found in inhibitory synapses. In live cultured hippocampal neurons, b-Aβo formed membrane-associated clusters, approximately 50% of which were located near synapses (which were identified by staining with the membrane dye FM4-64). With increasing incubation time, these clusters grew larger in size and showed decreased lateral diffusion. Aβo immunoprecipitations contained the metabotropic glutamate receptor 5 (mGluR5), suggesting that Aβo associated with neuronal membranes through binding to mGluR5. Aβo association with neurons was decreased with incubation with an antibody directed against mGluR5, but not ones against mGluR1 or mGluR2. In addition, hippocampal neurons from mGluR5–/– and mGluR5+/– showed decreased Aβo binding. In wild-type neurons incubated with Aβo, mGluR5 clusters were increased in size, were more likely to be localized to synapses, and showed slower diffusion. Application of Aβo increased intracellular calcium concentrations, suggesting that Aβo-induced clustering activated mGluR5 (which, through coupling to Gq, can increase intracellular calcium concentrations). This effect was blocked by the mGluR5 noncompetitive antagonist SIB1757 or the mGluR5 antibody. The authors propose that therapies to block the clustering of Aβo or to target mGluR5 activity could be developed to treat Alzheimers disease.
M. Renner, P. N. Lacor, P. T. Velasco, J. Xu, A. Contractor, W. L. Klein, A. Triller, Deleterious effects of amyloid β oligomers acting as an extracellular scaffold for mGluR5. Neuron 66, 739–754 (2010). [Online Journal]
Citation: W. Wong, Toxic Clusters. Sci. Signal. 3, ec181 (2010).
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