Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-β protein (Aβ) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Aβ from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Aβ dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Aβ N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Aβ dimers, suggesting that plaque cores are largely inactive but sequester Aβ dimers that are synaptotoxic. We conclude that soluble Aβ oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.
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We thank Elan for the gifts of 2G3 and 21F12 antibodies. Mass spectrometry was performed by the Taplin Biological Mass Spectrometry Facility (S. Gygi). We thank X. Sun and W. Qiu for performing ELISA. We thank members of the Selkoe laboratory for helpful comments. G.M.S. recognizes L. Gurumani for support and encouragement. This work was supported by the US National Institute on Aging grant AG R01 027443 (D.J.S., G.M.S., S.L., T.H.M., N.E.S.), Science Foundation Ireland grant 03/IN3/B403C (C.M.R., A.G.-M.) and Wellcome Trust grant 067660 (D.M.W., I.S.). B.L.S. was supported by the McKnight and Ellison Foundations as well as by a Lefler Small Grant Fund.
D.J.S. is a founding scientist of Athena Neurosciences and consultant to Elan.
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Shankar, G., Li, S., Mehta, T. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14, 837–842 (2008). https://doi.org/10.1038/nm1782
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