The chaperone DNAJB6b halts amyloid formation through association with transient Aβ oligomers.

Oligomers are transient toxic species in amyloidoses such as Alzheimer's disease. The binding of oligomers by human chaperone proteins has been inferred from the lack of detectable interactions with monomeric amyloid proteins and delay of fibril formation at sub-stoichiometric chaperone to monomer molar ratios. In this study, we provide direct experimental evidence for the binding of the human chaperone DNAJB6b (JB6) to amyloid peptide oligomers formed during an ongoing fibril formation process leading to the stabilization of these transient species. JB6 is a potent inhibitor of the aggregation of multiple amyloid peptides and here we observe the inhibition of the model amyloid-β (Aβ) 20-34 peptide at an astounding sub-stoichiometric 1 : 100 000 ratio of chaperone to amyloid peptide. Through microfluidic diffusional sizing, we detect an increase in the average hydrodynamic radius of JB6 when added to the supernatant of samples withdrawn from an ongoing fibril formation process, implying an interaction with transient non-monomeric Aβ20-34 and Aβ42 species, which we interpret as oligomers. Furthermore, the oligomer stability towards dissociation was studied using the same method. The results imply that JB6 stabilizes the oligomers against dissociation.