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

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

SUBMITTER: Lee MC 

PROVIDER: S-EPMC5859292 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other