Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition.

ABSTRACT: The triggers of late-onset sporadic Alzheimer's disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in ?-amyloid peptide (A?) is not studied sufficiently. Zinc-induced oligomerization of A? represents a potential seeding mechanism for the formation of neurotoxic A? oligomers and aggregates. Phosphorylation of A? by Ser8 (pS8-A?), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of A?, and moreover pS8-A? suppresses zinc-driven aggregation of non-modified A? in an equimolar mixture. We have further analyzed the effect of pS8-A? on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified A? that has no influence on the amyloidosis progression in murine models of AD, pS8-A? injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by A?, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of A? are neutralized by its phosphorylation.

SUBMITTER: Barykin EP 

PROVIDER: S-EPMC6123382 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature