The effect of the neuroprotector isatin on complex formation of beta-amyloid peptide fragments with some intracellular proteins

Abstract

Amyloid-b peptide (1-42) (Ab 1-42 ) is a key player in the development and progression of Alzheimer's disease (AD) and related pathologies, determined by formation of protein aggregates in the central nervous system. Ab 1-42 binding to crucial intracellular targets (and their subsequent inactivation) obviously represents one of the earliest events preceding extracellular pathogenic oligomerization/aggregation of Ab 1-42 . It is reasonable to expect that dissociation of the Ab 1-42 complexes with intracellular proteins by means of inhibitors followed by subsequent degradation of Ab 1-42 would not only protect critically important proteins but also prevent intracellular accumulation of Ab 1-42 . The aim of this study was to investigate the effect of the neuroprotector isatin (100 mM) on interaction of known Ab-binding proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase, with Ab 1-42 and its fragments (Ab 1-28 , Ab 12-28 , Ab 25-35 ). Ab 1-42 and its fragments (Ab 1-28 , Ab 12-28 , Ab 25-35 ) immobilized on the Biacore optical biosensor chip interacted with GAPDH and pyruvate kinase. The lowest and basically equal K d values were determined for GAPDH and pyruvate kinase complexes with immobilized Ab 1-42 and Ab25-35. The presence of 100 mM isatin caused a significant (more than fivefold) increase in the K d values for GAPDH complexes with all Ab peptides except Ab 1-28 . In contrast to GAPDH isatin increased dissociation of pyruvate kinase complexes only with Ab 1-42 (causing a 30-fold increase in K d ) and to a lesser extent with Ab 12-28 and Ab 25-35 (a 10-fold increase in K d ). It should be noted that in the presence of isatin the K d values for GAPDH and pyruvate kinase complexes with all Ab studied were in a narrower concentration range (10 -7 M - 10 -6 M) than in the absence of this neuroprotector (10 -8 M - 10 -6 M). Data obtained suggest existence of principal possibility of (pharmacological) protection of crucial intracellular targets against both Ab 1-42 , and its aggressive truncated peptides (Ab 25-35 ).