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Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model

Abstract

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid β peptide (Aβ) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease–like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Aβ pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease–like phenotype, support the idea that the accumulation of Aβ oligomers has a central role in the pathogenesis of Alzheimer disease.

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Figure 1: Cyclohexanehexols improve behavior in TgCRND8 mice.
Figure 2: Cyclohexanehexols improve pathological characteristics in TgCRND8 mice.
Figure 3: Spatial reference memory test was performed in 6-month-old mice after 28 d of treatment, beginning at 5 months of age (n = 10 mice per treatment arm).
Figure 4: Dot-blot analyses of soluble oligomeric Aβ in TgCRND8 left untreated or treated with epi-cyclohexanehexol (a) or scyllo-cyclohexanehexol (b).
Figure 5: Dose-dependent effects of scyllo-cyclohexanehexol on 4-month-old TgCRND8 mice.

Notes

  1. 1.

    NOTE: In the version of this article initially published online, there was an error in Table 1. In the 6-month prophylactic study under Scyllo-cyclohexanehexol, the soluble Aβ40 level should be 105 ± 8 instead of 1,105 ± 8. The error has been corrected for the HTML and print versions of the article.

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Acknowledgements

The authors thank C. Glabe for the oligomeric specific antibody, P. Mathews for the C1/6.1 antibody and R. Ahrens and P. Horne for technical assistance. The authors acknowledge support from the Ontario Alzheimer's Society (to H.T.J.M., P.H., P.E.F., D.W., J.M.), Canadian Institutes of Health Research (to H.T.J.M., P.H., P.E.F., D.W., J.M.), the Natural Sciences and Engineering Research Council of Canada (to J.M.), Canadian Foundation for Innovation (to H.T.J.M., P.H., P.E.F., D.W., J.M.), Ontario Research and Development Challenge Fund (to J.M., P.H., D.W., P.E.F.) Howard Hughes Medical Institute (to P.H.) and the Scottish Rite and Cryptic Foundations (to J.M.).

Author information

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Authors

Contributions

J.M., A.L.P., H.T.J.M. and P.S.G.-H. designed research. M.E.K., M.E.B., C.A.H., M.H.L.L., A.A.D., J.E.C., J.E.F., M.F.L., F.C. and S.S.N.W. performed research. J.M., M.E.K., C.A.H., A.L.P. and H.T.J.M. analyzed the data. J.M., H.T.J.M., P.E.F., D.W. and P.S.G.-H. wrote the manuscript.

Corresponding author

Correspondence to JoAnne McLaurin.

Ethics declarations

Competing interests

JoAnne McLaurin, Paul E. Fraser, David Westaway and Peter St. George-Hyslop and the University of Toronto have licensed this technology to a private-sector company from which support for a research program is derived.

JoAnne McLaurin is named as inventor on patent applications relating to this technology.

Supplementary information

Supplementary Fig. 1

Cyclohexanehexol stereoisomer structures. (PDF 16 kb)

Supplementary Fig. 2

Spatial reference memory version of the Morris water maze test in 6-month-old TgCRND8 mice untreated and treated with mannitol. (PDF 98 kb)

Supplementary Fig. 3

At 6 months of age, the plaque burden and astrogliosis in TgCRND8 mice untreated, epi- and scyllo-cyclohexanehexoltreated mice were examined. (PDF 240 kb)

Supplementary Fig. 4

A cue test was performed at the end of the spatial memory version of the Morris water maze test. (PDF 25 kb)

Supplementary Fig. 5

In vitro γ-secretase assay in HEK293 cells trasfected with human PPswe. (PDF 143 kb)

Supplementary Table 1

Overall effect of cyclohexanehexols on cognitive function. (PDF 26 kb)

Supplementary Methods (PDF 31 kb)

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McLaurin, J., Kierstead, M., Brown, M. et al. Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 12, 801–808 (2006). https://doi.org/10.1038/nm1423

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