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Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-β oligomers

Authors

  • Matthew Townsend PhD,

    1. Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
    Current affiliation:
    1. Merck Research Laboratories—Boston, Boston, MA 02115
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    • M.T. and J.P.C. contributed equally to this work.

  • James P. Cleary PhD,

    1. Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN
    2. Department of Psychology, University of Minnesota, Minneapolis, MN
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    • M.T. and J.P.C. contributed equally to this work.

  • Tapan Mehta BS,

    1. Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
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  • Jacki Hofmeister VT,

    1. Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN
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  • Sylvain Lesne PhD,

    1. Department of Neurology, University of Minnesota, Minneapolis, MN
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  • Eugene O'Hare PhD,

    1. School of Psychology, Queen's University, Belfast, United Kingdom
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  • Dominic M. Walsh PhD,

    1. Laboratory for Neurodegenerative Research, Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Dublin, Republic of Ireland
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  • Dennis J. Selkoe MD

    Corresponding author
    1. Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
    • Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115
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Abstract

Objective

Despite progress in defining a pathogenic role for amyloid β protein (Aβ) in Alzheimer's disease, orally bioavailable compounds that prevent its effects on hippocampal synaptic plasticity and cognitive function have not yet emerged. A particularly attractive therapeutic strategy is to selectively neutralize small, soluble Aβ oligomers that have recently been shown to mediate synaptic dysfunction.

Methods

Using electrophysiological, biochemical, and behavioral assays, we studied how scyllo-inositol (AZD-103; molecular weight, 180) neutralizes the acutely toxic effects of Aβ on synaptic function and memory recall.

Results

Scyllo-inositol, but not its stereoisomer, chiro-inositol, dose-dependently rescued long-term potentiation in mouse hippocampus from the inhibitory effects of soluble oligomers of cell-derived human Aβ. Cerebroventricular injection into rats of the soluble Aβ oligomers interfered with learned performance on a complex lever-pressing task, but administration of scyllo-inositol via the drinking water fully prevented oligomer-induced errors.

Interpretation

A small, orally available natural product penetrates into the brain in vivo to rescue the memory impairment produced by soluble Aβ oligomers through a mechanism that restores hippocampal synaptic plasticity. Ann Neurol 2006;60:668–676

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