As molecular research into Alzheimer disease shifts increasingly toward analysis of soluble oligomers of the amyloid-β (Aβ) peptide, scientists are looking for therapeutic strategies to interfere with these oligomers in vivo. The gold standard is still a pill that a person will be able to swallow and be sure its effect reaches across the blood-brain barrier to the brain’s beleaguered synapses, where Aβ oligomers are thought to do their dirty work. One such compound, scyllo-inositol or AZD-103, drew attention last summer when Canadian researchers described its effect on amyloid deposition and water maze performance in transgenic mice (see McLaurin et al., 2006). Now, this story took another step forward with a report by Mathew Townsend and colleagues from Brigham and Women’s Hospital in Boston and elsewhere, who tested scyllo-inositol in their own experimental systems to study the effects of Aβ oligomers.
In the December 22 Annals of Neurology, the scientists report that scyllo-inositol rescued the impairment of synaptic function in slices of wild-type mouse hippocampus that the researchers had previously described. It also restored the flagging performance of normal adult rats in a lever pressing behavioral task that the scientists had previously established to characterize the effect of Aβ oligomers in vivo. Both experiments use Aβ dimers, trimers, and tetramers released by cultured cells, not synthetic Aβ. The study acknowledges support from the Canadian biotech company Transition Therapeutics, which is testing AZD-103 for human use as an AD drug. According to the company’s website, an initial phase 1 safety study ended without side effects, a second one testing higher doses is underway, and the much larger pharmaceutical company Elan recently partnered with Transition Therapeutics to develop AZD-103.—Gabrielle Strobel
- McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, Darabie AA, Cousins JE, French JE, Lan MF, Chen F, Wong SS, Mount HT, Fraser PE, Westaway D, St George-Hyslop P. Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006 Jul;12(7):801-8. PubMed.
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- Townsend M, Cleary JP, Mehta T, Hofmeister J, Lesne S, O'Hare E, Walsh DM, Selkoe DJ. Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers. Ann Neurol. 2006 Dec;60(6):668-76. PubMed.