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The Journal of Neuroscience, March 14, 2007, 27(11):2866-2875; doi:10.1523/JNEUROSCI.4970-06.2007
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Neurobiology of Disease
Natural Oligomers of the Alzheimer Amyloid-ß Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway
Ganesh M. Shankar,1,2 Brenda L. Bloodgood,1 Matthew Townsend,2 Dominic M. Walsh,3 Dennis J. Selkoe,2 andBernardo L. Sabatini1 1Department of Neurobiology, Harvard Medical School, and 2Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and 3Laboratory for Neurodegenerative Research, University College Dublin, Dublin 4, Republic of Ireland
Correspondence should be addressed to either of the following: Dennis J. Selkoe at the above address, Email: dselkoe{at}rics.bwh.harvard.edu; or Bernardo L. Sabatini at the above address, Email: bsabatini{at}hms.harvard.edu
Alzheimer's disease (AD) is characterized by decreased synapse density in hippocampus and neocortex, and synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-ß protein (Aß) in AD, a direct link between a specific form of Aß and synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Aß dimers and trimers, but not monomers, induce progressive loss of hippocampal synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Aß-specific antibodies or a small-molecule modulator of Aß aggregation. Mechanistically, Aß-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Aß oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human Aß trigger synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Aß-induced neuronal dysfunction.
Key words: amyloid-ß protein; Alzheimer's disease; dendritic spine; synapse loss; NMDA receptor; calcineurin
Received Nov. 15, 2006; revised Feb. 5, 2007; accepted Feb. 5, 2007.
Correspondence should be addressed to either of the following: Dennis J. Selkoe at the above address, Email: dselkoe{at}rics.bwh.harvard.edu; or Bernardo L. Sabatini at the above address, Email: bsabatini{at}hms.harvard.edu
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