title: Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Townsend
authors.forename: James P
authors.initials: JP
authors.lastname: Cleary
authors.forename: Tapan
authors.initials: T
authors.lastname: Mehta
authors.forename: Jacki
authors.initials: J
authors.lastname: Hofmeister
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lesne
authors.forename: Eugene
authors.initials: E
authors.lastname: O'Hare
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007276:Injections, Intraventricular; D007294:Inositol / Q000494:pharmacology* / Q000627:therapeutic use; D007858:Learning / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C009217:scyllitol; D007294:Inositol