RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory (original) (raw)

Nature volume 440, pages 352–357 (2006)Cite this article

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Abstract

Memory function often declines with age1, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons2. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-β precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-β protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6–14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-β (refs 3–6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which we term Aβ*56 (Aβ star 56). Aβ*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Aβ*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

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Change history

Editor’s Note: The editors of Nature have been alerted to concerns regarding some of the figures in this paper. Nature is investigating these concerns, and a further editorial response will follow as soon as possible. In the meantime, readers are advised to use caution when using results reported therein.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41586-024-07691-8

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Acknowledgements

We thank S. Younkin, D. Walsh, M. Podlisny, D. Selkoe, J. Cleary and S. Prusiner for critical discussions. We are grateful to D. Cooper-Blacketer, J. McQuail and M. Sherman for technical help, and A. Delacourte and N. Sergeant for providing the APPC17-Cter antiserum. This work was supported by grants from the NIH (to K.H.A., M.G. and A.Y.) and a gift from M. and H. Hobbs to M.G. Author Contributions S.L. and K.H.A. conceived the project. S.L. planned, performed and analysed the biochemistry experiments, including the protein extractions and purification of Aβ*56. K.H.A. wrote most of the paper. M.T.K. and M.G. planned, performed and analysed the rat behavioural experiments, and L.K. planned and analysed the mouse behavioural experiments. A.Y. provided the mass spectrometry analysis of purified Aβ*56, C.G.G. provided biochemistry advice, and C.G.G. and R.K. donated the A11 antiserum.

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Authors and Affiliations

  1. Departments of Neurology,
    Sylvain Lesné, Linda Kotilinek & Karen H. Ashe
  2. Neuroscience,
    Karen H. Ashe
  3. Graduate Program in Neuroscience, University of Minnesota Medical School, Minnesota, 55455, Minneapolis, USA
    Karen H. Ashe
  4. Department of Psychological and Brain Sciences, Johns Hopkins University, Maryland, 21218, Baltimore, USA
    Ming Teng Koh & Michela Gallagher
  5. Geriatric Research Education Clinical Center, Minneapolis VA Medical Center, Minnesota, 55417, Minneapolis, USA
    Karen H. Ashe
  6. Department of Molecular Biology and Biochemistry, University of California, California, 92697, Irvine, USA
    Rakez Kayed & Charles G. Glabe
  7. Department of Pharmaceutical Sciences, University of Southern California, California, 90089, Los Angeles, USA
    Austin Yang

Authors

  1. Sylvain Lesné
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  2. Ming Teng Koh
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  3. Linda Kotilinek
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  4. Rakez Kayed
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  5. Charles G. Glabe
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  6. Austin Yang
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  7. Michela Gallagher
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  8. Karen H. Ashe
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Corresponding author

Correspondence toKaren H. Ashe.

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Competing interests

S.L. and K.H.A. are inventors on a patent application submitted by the University of Minnesota that describes Aβ*56.

Supplementary information

Supplementary Notes

This file contains the Supplementary Methods, Supplementary Discussion (on the selective effects of Aβ*56 on retention, but not acquisition of spatial memory) Supplementary Table 1, Supplementary Figures 1–7 and additional references. (PDF 2010 kb)

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Lesné, S., Koh, M., Kotilinek, L. et al. RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory.Nature 440, 352–357 (2006). https://doi.org/10.1038/nature04533

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Editorial Summary

Early Warning Of Alzheimer's

Poor memory function has been noted in individuals that developed Alzheimer's disease up to 15 years before the eventual diagnosis of the condition. Experiments in a mouse model for the disease have now tracked down a possible cause for this early symptom: the extracellular accumulation of a soluble amyloid-β peptide assembly, dubbed Aβ*. When Aβ* is isolated from these mice and injected into rats, the rats also experience temporary memory deterioration independent of plaque formation or neuronal loss, the classic hallmarks of Alzheimer's. This work points to Aβ* as a potential diagnostic, and raises the possibility that by targeting it early it may be possible to prevent or delay the permanent changes characteristic of the later stages of the disease.

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