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

FRONTIERS IN MOLECULAR NEUROSCIENCE(2018)

Cited 30|Views25
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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 beta-amyloid peptide (A beta) is not studied sufficiently. Zinc-induced oligomerization of A beta represents a potential seeding mechanism for the formation of neurotoxic A beta oligomers and aggregates. Phosphorylation of A beta by Ser8 (pS8-A beta), 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 beta, and moreover pS8-A beta suppresses zinc-driven aggregation of non-modified A beta in an equimolar mixture. We have further analyzed the effect of pS8-A beta 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 beta that has no influence on the amyloidosis progression in murine models of AD, pS8-A beta 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 beta, 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 beta are neutralized by its phosphorylation.
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Key words
Alzheimer's disease,beta-amyloid,Na+,K+-ATPase,zinc,protein phosphorylation,amyloid plaques,aggregation,metal-binding domain
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