Small molecule β-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer’s disease
β-Amyloid (Aβ) peptides are thought to play a major role in the pathogenesis of Alzheimer’s disease. Compounds that disrupt the kinetic pathways of Aβ aggregation may be useful in elucidating the role of oligomeric, protofibrillar and fibrillar Aβ in the etiology of the disease. We have previously reported that scyllo-inositol inhibits Aβ42 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–Aβ binding. We report here that all scyllo-inositol derivatives demonstrated reduced effectiveness in preventing Aβ42 fibrillization compared with scyllo-inositol, suggesting that scyllo-inositol interacts with Aβ42 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 Aβ42 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 Aβ aggregation can be targeted at multiple points along the kinetic pathway for the improvement of Alzheimer’s disease-like pathology.
Document Type: Research Article
Affiliations: 1: Centre for Research in Neurodegenerative Diseases, University of Toronto, 6 Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada 2: Department of Chemistry, University of Toronto, Toronto, ON, Canada
Publication date: 01 January 2010