Letter | Published:

A specific amyloid-β protein assembly in the brain impairs memory

Nature volume 440, pages 352357 (16 March 2006) | Download Citation



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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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.

Author information


  1. Departments of Neurology and

    • Sylvain Lesné
    • , Linda Kotilinek
    •  & Karen H. Ashe
  2. Neuroscience, and

    • Karen H. Ashe
  3. Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA

    • Karen H. Ashe
  4. Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, Maryland 21218, USA

    • Ming Teng Koh
    •  & Michela Gallagher
  5. Geriatric Research Education Clinical Center, Minneapolis VA Medical Center, Minneapolis, Minnesota 55417, USA

    • Karen H. Ashe
  6. Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA

    • Rakez Kayed
    •  & Charles G. Glabe
  7. Department of Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, USA

    • Austin Yang


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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.

Corresponding author

Correspondence to Karen H. Ashe.

Supplementary information

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  1. 1.

    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.

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