The effect of a newly characterized small molecule on Alzheimer’s disease-related amyloid-β (Aβ) oligomers supports the hypothesis that the oligomers are more toxic than mature amyloid fibrils. The finding could help the search for effective Alzheimer’s treatments.
Identified by Erich E. Wanker of the Max Delbrück Center for Molecular Medicine, in Berlin, and coworkers, the small molecule accelerates the conversion of Aβ oligomers into mature fibrils and reduces the oligomers’ toxicity in cell-based assays (Nat. Chem. Biol., DOI: 10.1038/nchembio.719).
When they added the phenoxazone derivative, dubbed O4, to a solution of Aβ oligomers, the mixture quickly formed amyloid fibrils. In cell-based assays, brain cells cultured with both soluble Aβ oligomers and O4 were protected from damage.
The researchers suggest that O4, which binds hydrophobic amino acids on Aβ peptides, stimulates the formation of fibrils by increasing the surface hydrophobicity of amyloid oligomers and easing aggregation.
Ronald Wetzel, an amyloid expert at the University of Pittsburgh School of Medicine, says that “the work appears to validate the concept that acceleration of the formation of mature fibrils might be therapeutically beneficial in reducing the steady state of more toxic oligomers.” He advises caution, however. “It remains to be seen whether an approach that purposefully encourages brain amyloid formation will prove therapeutically successful,” he says.