title: CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity.
abstract: Soluble and toxic oligomers of amyloid beta (A beta) protein have been identified as the true neurotoxic species involved in Alzheimer's disease and considering them as targets to inhibit A beta aggregation might have a therapeutic value. We previously set up a CE method that enables the separation and quantification of transient oligomers of A beta protein-containing 42 amino acids (A beta(1-42)) along the pathway leading to fibrils and we now demonstrate how this method can be successfully applied to examine the in vitro inhibitory effects of small molecules on A beta oligomerization. To this end, we investigated mitoxantrone and pixantrone, two well-known anticancer drugs, as well as suramin and a suramin-like compound. By using CE, it is here shown how mitoxantrone and pixantrone either reduce or block A beta(1-42) oligomerization, while Thioflavin T spectrofluorimetric assay and transmission electron microscopy demonstrate how these two compounds also display antifibrillogenic activity. Interestingly, in vitro cell viability experiments indicated that pixantrone significantly reduces A beta(1-42) neurotoxicity.
authors.affiliation: Dipartimento di Chimica Farmaceutica, University of Pavia, Pavia, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Colombo
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanni
authors.forename: Laura
authors.initials: L
authors.lastname: Verga
authors.forename: Gabriele
authors.initials: G
authors.lastname: Caccialanza
authors.forename: Ersilia
authors.initials: E
authors.lastname: De Lorenzi
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019075:Electrophoresis, Capillary / Q000379:methods*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D008942:Mitoxantrone / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010316:Particle Size; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D058225:Plaque, Amyloid / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D013050:Spectrometry, Fluorescence; D013498:Suramin / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D007546:Isoquinolines; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T; D013498:Suramin; D008942:Mitoxantrone; C086548:pixantrone