CE can identify small molecules that selectively target soluble oligomers of amyloid beta protein and display antifibrillogenic activity.
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.
Colombo
Raffaella
R
Dipartimento di Chimica Farmaceutica, University of Pavia, Pavia, Italy.
Carotti
Angelo
A
Catto
Marco
M
Racchi
Marco
M
Lanni
Cristina
C
Verga
Laura
L
Caccialanza
Gabriele
G
De Lorenzi
Ersilia
E
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
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