The Features of Beta-Amyloid Phosphorylation in Alzheimer's Disease.

Abstract

Accumulation of neurotoxic aggregates of beta-amyloid peptides (Aβ) is a hallmark of Alzheimer's disease (AD) progression. Post-translational modifications (PTMs) increase Aβ aggregation and cytotoxicity, and the content of specific Aβ proteoforms is elevated in senile plaques of AD patients. The pathophysiological mechanisms of aggregate formation and the role of Aβ proteoforms need thorough study both to understand the role played by specific processes in the initiation of neuronal degradation and to find effective preventive means of therapeutic action. The present work investigates the dynamics of accumulation of phosphorylated serine-8 proteoform Aβ (pSer8-Aβ) using the 5xFAD mouse amyloid model. Aβ samples from human cerebrospinal fluid (CSF) and brain were also investigated. Western blot studies using 1E4E11 and 4G8 antibodies showed that accumulation of pSer8-Aβ in mouse brain starts as early as at the age of 3 months and reaches a maximum by the age of 14-17 months, which is generally similar to the dynamics of accumulation of the total pool of Aβ peptides. The pSer8-Aβ level in human CSF in AD patients can reach ~ 1-10% of the total amount of Aβ. Mass spectrometric analysis showed that Aβ phosphorylation by the Ser8, Tyr10, and Ser26 residues in brain tissues, as well as phosphorylation of the APP by Thr719 residue, is possible. These findings support the assumption that pSer8-Aβ proteoforms are involved in amyloidosis in AD. KEYWORDS Beta-amyloid, mass spectrometry, Alzheimer's disease, phosphorylation.