Per-6-substituted beta-cyclodextrin libraries inhibit formation of beta-amyloid-peptide (A beta)-derived, soluble oligomers

• Published in: Journal of molecular neuroscience 2002-08, Vol.19 (1-2), p.51-55
• Main Authors: Yu, Jiaxin, Bakhos, Lara, Chang, Lei, Holterman, Mark J, Klein, William L, Venton, Duane L
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Peptides - chemistry; Animals; beta-Cyclodextrins; Blotting, Western; Cyclodextrins - biosynthesis; Cyclodextrins - chemistry; Cyclodextrins - metabolism; Immunoblotting; Peptide Fragments - biosynthesis; Peptide Fragments - chemistry; Rabbits; Time Factors
• ISSN: 0895-8696; 1559-1166
• DOI: 10.1007/s12031-002-0010-x

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 A beta(1-42). While large neurotoxic amyloid fibrils have been known for years, recent studies show that soluble protofibril and A beta(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 microM total library, inhibited ADDLs formation (10 nM A beta(1-42)) over a period of 4 hours. The latter was confirmed by a western blot assay showing decreased amounts of the initially formed A beta(1-42) tetramer. These preliminary experiments suggest that derivatized forms of beta-CD can interfere with the oligomerization process of A beta(1-42).