An orally available compound prevents deficits in memory caused by the Alzheimer amyloid-B oligomers.

M. Townsend, J.P. Cleary, T. Mehta, J. Hofmeister, S. Lesne, Eugene O'Hare, D.M. Walsh, D.J. Selkoe

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Abstract

Despite progress in defining a pathogenic role for amyloid beta protein (Abeta) 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 Abeta 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 Abeta 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 Abeta. Cerebroventricular injection into rats of the soluble Abeta 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 Abeta oligomers through a mechanism that restores hippocampal synaptic plasticity.
Original languageEnglish
Pages (from-to)668-676
Number of pages9
JournalAnnals of Neurology
Volume60(6)
Issue number6
DOIs
Publication statusPublished - Dec 2006

ASJC Scopus subject areas

  • Neuroscience(all)

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    Townsend, M., Cleary, J. P., Mehta, T., Hofmeister, J., Lesne, S., O'Hare, E., Walsh, D. M., & Selkoe, D. J. (2006). An orally available compound prevents deficits in memory caused by the Alzheimer amyloid-B oligomers. Annals of Neurology, 60(6)(6), 668-676. https://doi.org/10.1002/ana.21051