Zinc ion rapidly induces toxic, off-pathway amyloid-beta oligomers distinct from amyloid-beta derived diffusible ligands in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly. Zinc (Zn) ion interacts with the pathogenic hallmark, amyloid-beta (A beta), and is enriched in senile plaques in brain of AD patients. To understand Zn-chelated A beta (ZnA beta) species, here we systematically characterized ZnA beta aggregates by incubating equimolar A beta with Zn. We found ZnA beta 40 and ZnA beta 42 both form spherical oligomers with a diameter of similar to 12-14 nm composed of reduced beta-sheet content. Oligomer assembly examined by analytical ultracentrifugation, hydrophobic exposure by BisANS spectra, and immunoreactivity of ZnA beta and A beta derived diffusible ligands (ADDLs) are distinct. The site-specific C-13 labeled solid-state NMR spectra showed that ZnA beta 40 adopts beta-sheet structure as in A beta 40 fibrils. Interestingly, removal of Zn by EDTA rapidly shifted the equilibrium back to fibrillization pathway with a faster kinetics. Moreover, ZnA beta oligomers have stronger toxicity than ADDLs by cell viability and cytotoxicity assays. The ex vivo study showed that ZnA beta oligomers potently inhibited hippocampal LTP in the wild-type C57BL/6JNarl mice. Finally, we demonstrated that ZnA beta oligomers stimulate hippocampal microglia activation in an acute A beta-injected model. Overall, our study demonstrates that ZnA beta rapidly form toxic and distinct off-pathway oligomers. The finding provides a potential target for AD therapeutic development.