Zinc ion rapidly induces toxic, off-pathway amyloid-ß oligomers distinct from amyloid-ß 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-ß (Aß), and is enriched in senile plaques in brain of AD patients. To understand Zn-chelated Aß (ZnAß) species, here we systematically characterized ZnAß aggregates by incubating equimolar Aß with Zn. We found ZnAß40 and ZnAß42 both form spherical oligomers with a diameter of ~12-14 nm composed of reduced ß-sheet content. Oligomer assembly examined by analytical ultracentrifugation, hydrophobic exposure by BisANS spectra, and immunoreactivity of ZnAß and Aß derived diffusible ligands (ADDLs) are distinct. The site-specific 13C labeled solid-state NMR spectra showed that ZnAß40 adopts ß-sheet structure as in Aß40 fibrils. Interestingly, removal of Zn by EDTA rapidly shifted the equilibrium back to fibrillization pathway with a faster kinetics. Moreover, ZnAß oligomers have stronger toxicity than ADDLs by cell viability and cytotoxicity assays. The ex vivo study showed that ZnAß oligomers potently inhibited hippocampal LTP in the wild-type C57BL/6JNarl mice. Finally, we demonstrated that ZnAß oligomers stimulate hippocampal microglia activation in an acute Aß-injected model. Overall, our study demonstrates that ZnAß rapidly form toxic and distinct off-pathway oligomers. The finding provides a potential target for AD therapeutic development.