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 Aβ1-42. While large neurotoxic amyloid fibrils have been known for years, recent studies show that soluble protofibril and Aβ1-42-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 β-cyclodextrin (β-CD) derivatives for inhibition of ADDLs formation. Libraries were prepared from per-6-iodo-β-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 μM total library, inhibited ADDLs formation (10 nM Aβ1-42) over a period of 4 hours. The latter was confirmed by a western blot assay showing decreased amounts of the initially formed Aβ1-42 tetramer. These preliminary experiments suggest that derivatized forms of β-CD can interfere with the oligomerization process of Aβ1-42.
- Beta amyloid
- Beta cyclodextrin
- Combinatorial chemistry
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience