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

14 July 2022 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.


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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Figure 1: Temporal patterns of soluble Aβ oligomers and memory decline in Tg2576 mice.
Figure 2: Biochemical properties of Aβ assemblies in Tg2576 mice.
Figure 3: Levels of the 56-kDa Aβ assembly show the strongest inverse correlation with spatial memory.
Figure 4: Purification of Aβ*56 from Tg2576 brain and effects of purified Aβ*56 on memory in young rats.

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  • 14 July 2022

    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.


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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.

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Correspondence to Karen H. Ashe.

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

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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. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).

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