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

• Published in: Frontiers in molecular neuroscience Vol. 11; p. 302
• Main Authors: Barykin, Evgeny P, Petrushanko, Irina Y, Kozin, Sergey A, Telegin, Georgy B, Chernov, Alexander S, Lopina, Olga D, Radko, Sergey P, Mitkevich, Vladimir A, Makarov, Alexander A
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 29.08.2018; Frontiers Media S.A
• Subjects: Age; Alzheimer's disease; Amyloidosis; Animal models; Disease; Enzymes; Hippocampus; Insects; Intravenous administration; K+-ATPase; Kinases; Laboratory animals; Light scattering; Na+; Na+/K+-exchanging ATPase; Neurodegeneration; Neuroscience; Neurosciences; Neurotoxicity; Oligomerization; Peptides; Phosphorylation; protein phosphorylation; Protein seeding; Senile plaques; Zinc; β-Amyloid; United States > US; Russia; Alzheimer’s disease; Na+; aggregation; K+-ATPase; metal-binding domain; protein phosphorylation; zinc; amyloid plaques; β-amyloid
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2018.00302

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 β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a potential seeding mechanism for the formation of neurotoxic Aβ oligomers and aggregates. Phosphorylation of Aβ by Ser8 (pS8-Aβ), 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 Aβ, and moreover pS8-Aβ suppresses zinc-driven aggregation of non-modified Aβ in an equimolar mixture. We have further analyzed the effect of pS8-Aβ 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 Aβ that has no influence on the amyloidosis progression in murine models of AD, pS8-Aβ injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na ,K -ATPase activity by Aβ, 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 Aβ are neutralized by its phosphorylation.