Journal
JOURNAL OF MOLECULAR NEUROSCIENCE
Volume 19, Issue 1-2, Pages 51-55Publisher
HUMANA PRESS INC
DOI: 10.1007/s12031-002-0010-x
Keywords
Alzheimer's; beta amyloid; ADDLs; beta cyclodextrin; combinatorial chemistry
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Alzheimer's disease is the most common cause of dementia in older individuals with compelling evidence favoring neuron dysfunction and death triggered by assembled forms of Abeta(1-42). While large neurotoxic amyloid fibrils have been known for years, recent studies show that soluble protofibril and Abeta(1-42)-derived diffusible ligands (ADDLs) may also be involved in neurotoxicity. In the present work, dot-blot immunoassays discriminating ADDLs from monomers were used to screen libraries of per-substituted beta-cyclodextrin (beta-CD) derivatives for inhibition of ADDLs formation. Libraries were prepared from per-6-iodo-beta-CD by treatment with various amine nucleophiles. The most active library tested (containing >2000 derivatives) was derived from imidazole, N, N-dimethylethylenediamine and furfurylamine, which at 10 muM total library, inhibited ADDLs formation (10 nM Abeta(1-42)) over a period of 4 hours. The latter was confirmed by a western blot assay showing decreased amounts of the initially formed Abeta(1-42) tetramer. These preliminary experiments suggest that derivatized forms of beta-CD can interfere with the oligomerization process of Abeta(1-42).
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