Clioquinol and other hydroxyquinoline derivatives inhibit Aβ(1-42) oligomer assembly

Soluble oligomeric amyloid-beta (A beta) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active compounds was robotically screened for inhibitors of A beta oligomer formation with a single-site biotinylated A beta(1-42) oligomer assembly assay. Several quinoline-like compounds were identified with IC50's <10 mu M, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism. The 2-OH, 4-OH, and 6-OH quinolines do not block A beta oligomer formation up to a concentration of 100 mu M. Analogs of clioquinol have shown activity in reducing A beta levels and improving behavioral deficits in mouse models of A beta pathology. The inhibitory effects of clioquinol and other 8-OH quinoline derivatives on oligomer formation in vitro are unrelated to their chelating activity. Crosslinking studies suggest that clioquinol acts at the stage of trimer formation. These preliminary data may suggest that 8-OH quinolines have the potential for suppressing A beta oligomer formation which should be considered when assessing the effects of these compounds in animal models and clinical trials. (C) 2009 Elsevier Ireland Ltd. All rights reserved.