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Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

Nature Medicine volume 14, pages 837842 (2008) | Download Citation

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Abstract

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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Change history

  • 15 July 2008

    Nature Medicine; doi:10.1038/nm1782; published online 22 June 2008; corrected 15 July 2008. In the version of this article initially published online, the authors inadvertently included the blot in Figure 1b (right) a second time as Figure 1a (right). In addition, the authors would like to clarify the white areas within Figure 3a (top and bottom) in the figure legend. These errors have been corrected for all versions of the article.

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Acknowledgements

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.

Author information

Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.

    • Ganesh M Shankar
    • , Shaomin Li
    • , Tapan H Mehta
    • , Nina E Shepardson
    • , Cynthia A Lemere
    •  & Dennis J Selkoe
  2. Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.

    • Ganesh M Shankar
    •  & Bernardo L Sabatini
  3. School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland.

    • Amaya Garcia-Munoz
    •  & Ciaran M Regan
  4. Laboratory for Neurodegenerative Research, University College Dublin, Dublin 4, Ireland.

    • Imelda Smith
    •  & Dominic M Walsh
  5. Department of Pathology, Beaumont Hospital and Royal College of Surgeons Ireland, Dublin 9, Ireland.

    • Francesca M Brett
    •  & Michael A Farrell
  6. Trinity College Institute of Neuroscience and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.

    • Michael J Rowan

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Contributions

G.M.S. designed and performed experiments and prepared the manuscript; S.L. designed and performed electrophysiology experiments; T.H.M. and N.E.S. performed biochemical experiments; A.G.-M. performed passive avoidance experiments; I.S. generated mutant Aβ peptide; C.A.L., F.M.B. and M.A.F. characterized human brain tissue; M.J.R. designed electrophysiology experiments; C.M.R. designed passive avoidance experiments; D.M.W. designed biochemical experiments; B.L.S. designed electrophysiology and morphology experiments; and D.J.S. designed experiments and prepared the manuscript.

Competing interests

D.J.S. is a founding scientist of Athena Neurosciences and consultant to Elan.

Corresponding author

Correspondence to Dennis J Selkoe.

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    Supplementary Text and Figures

    Supplementart Figs. 1–7, Supplementary Table 1 and Supplementary Methods

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DOI

https://doi.org/10.1038/nm1782

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