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

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