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 or 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.