Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 31, Issue 2, Pages 203-213Publisher
WILEY
DOI: 10.1111/j.1460-9568.2009.07052.x
Keywords
hydrogen bonding; hydrophobicity; Morris water maze; scyllo-inositol; TgCRND8 mice
Categories
Funding
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Ontario Alzheimer Society
- Alzheimer's Society of Canad
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beta-Amyloid (A beta) peptides are thought to play a major role in the pathogenesis of Alzheimer's disease. Compounds that disrupt the kinetic pathways of A beta aggregation may be useful in elucidating the role of oligomeric, protofibrillar and fibrillar A beta in the etiology of the disease. We have previously reported that scyllo-inositol inhibits A beta(42) fibril formation but the mechanism(s) by which this occurs has not been investigated in detail. Using a series of scyllo-inositol derivatives in which one or two hydroxyl groups were replaced with hydrogen, chlorine or methoxy substituents, we examined the role of hydrogen bonding and hydrophobicity in the structure-function relationship of scyllo-inositol-A beta binding. We report here that all scyllo-inositol derivatives demonstrated reduced effectiveness in preventing A beta(42) fibrillization compared with scyllo-inositol, suggesting that scyllo-inositol interacts with A beta(42) via key hydrogen bonds that are formed by all hydroxyl groups. Increasing the hydrophobicity of scyllo-inositol by the addition of two methoxy groups (1,4-di-O-methyl-scyllo-inositol) produced a derivative that stabilized A beta(42) protofibrils in vitro. Prophylactic administration of 1,4-di-O-methyl-scyllo-inositol to TgCRND8 mice attenuated spatial memory impairments and significantly decreased cerebral amyloid pathology. These results suggest that A beta aggregation can be targeted at multiple points along the kinetic pathway for the improvement of Alzheimer's disease-like pathology.
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