New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease.
The amyloid hypothesis suggests that the process of amyloid-beta protein (Abeta) fibrillogenesis is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of Alzheimer's disease. Consequently, preventing this process might provide a viable therapeutic strategy for slowing and/or preventing the progression of this devastating disease. A promising strategy to achieve prevention of this disease is to discover compounds that inhibit Abeta polymerization and deposition. Herein, we describe a new class of small molecules that inhibit Abeta aggregation, which is based on the chemical structure of apomorphine. These molecules were found to interfere with Abeta1-40 fibrillization as determined by transmission electron microscopy, Thioflavin T fluorescence and velocity sedimentation analytical ultracentrifugation studies. Using electron microscopy, time-dependent studies demonstrate that apomorphine and its derivatives promote the oligomerization of Abeta but inhibit its fibrillization. Preliminary structural activity studies demonstrate that the 10,11-dihydroxy substitutions of the D-ring of apomorphine are required for the inhibitory effectiveness of these aporphines, and methylation of these hydroxyl groups reduces their inhibitory potency. The ability of these small molecules to inhibit Abeta amyloid fibril formation appears to be linked to their tendency to undergo rapid autoxidation, suggesting that autoxidation product(s) acts directly or indirectly on Abeta and inhibits its fibrillization. The inhibitory properties of the compounds presented suggest a new class of small molecules that could serve as a scaffold for the design of more efficient inhibitors of Abeta amyloidogenesis in vivo.
Lashuel
Hilal A
HA
Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, Cambridge, Massachusetts 02139, USA. hlashuel@hms.harvard.edu
Hartley
Dean M
DM
Balakhaneh
David
D
Aggarwal
Aneel
A
Teichberg
Saul
S
Callaway
David J E
DJ
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000648:ultrastructure; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008854:Microscopy, Electron; D008954:Models, Biological; D020836:Protein Structure, Quaternary; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D013844:Thiazoles; C009462:thioflavin T; D001058:Apomorphine