Chemical modifications of amyloid-β(1-42) have a significant impact on the repertoire of brain amyloid-β(1-42) binding proteins

The amyloid-beta peptide(1-42) (A beta) is a key player in the development and progression of Alzheimer's disease (AD). Although much attention is paid to its role in formation of extracellular amyloid plaques and protein aggregates as well as to corresponding mechanisms of their toxicity, good evidence exists that intracellular A beta can accumulate intraneuronally and interact with intracellular target proteins. However, intracellular A beta binding proteins as well as conditions favoring their interactions with A beta are poorly characterized. In this study we have investigated the effect of two known pathogenic A beta modifications, isomerization of Asp7 and phosphorylation of Ser8, on the proteomic profiles of mouse brain A beta binding proteins. Phosphorylation of Ser8 and especially isomerization of Asp7 significantly extended the repertoire of mouse brain A beta binding proteins. However, there were 61 proteins, common for three types of the affinity ligands. They obviously represent potential targets for direct interaction with all A beta species. Taking into consideration spontaneous mode of Asp7 isomerization and reports on initial accumulation of phosphorylated A beta species inside neurons it is reasonable to suggest that these modifications of intracellular A beta peptides causing the significant increase in the repertoire of A beta binding proteins represent a primary pathogenic effect that precedes formation of extracellular pathogenic oligomerization/aggregation of A beta peptides well described in the literature. (C) 2016 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.