Per-6-substituted beta-cyclodextrin libraries inhibit formation of beta-amyloid-peptide (A beta)-derived, soluble oligomers.
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).
Yu
Jiaxin
J
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The University of Illinois at Chicago, 60612, USA.
Bakhos
Lara
L
Chang
Lei
L
Holterman
Mark J
MJ
Klein
William L
WL
Venton
Duane L
DL
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D003505:Cyclodextrins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D015151:Immunoblotting; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry; D011817:Rabbits; D013997:Time Factors; D047392:beta-Cyclodextrins
D016229:Amyloid beta-Peptides; D003505:Cyclodextrins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D047392:beta-Cyclodextrins; C031215:betadex