Arginine metabolising enzymes as targets against Alzheimers' disease

Abstract

Even though the accumulation of arginine and the deposit of aggregated Aβ-peptides (senile plaques) in the brain of an Alzheimer patient are classic points of evidence in the neuropathology of the disease considerable dispute remains on their method of formation. One acceptable mechanism to initiate events is a 'seed' aggregation of free monomeric peptides into toxic soluble amyloid oligomers and subsequently into deposits of insoluble fibrils. Since all of these events take place in the brain astrocytes it suggests an interference between arginine-metabolising enzymes and the Aβ-peptides. Through kinetic, fluorimetric and thermodynamic analyses two such enzymes - neuronal nitric oxide synthase and peptidyl arginine deiminase - are, not only inhibited by structural fragments of Aβ1-42 but are catalytic towards fibrillogenesis. The interaction of the peptide fragments with each enzyme is endothermic, non-spontaneous and involves hydrophobic-hydrophobic associations with a single binding site. The trigger for this series of events focusses in particularly on Aβ17-21 with two phenylalanines [Phe19; Phe20], the three glycine zipper motifs [Aβ25-29; Aβ29-33; Aβ33-37] and the triple sequence [Aβ25-37] that includes two isoleucine residues [Ile31; Ile32]. FRET studies show the Aβ-peptide fragments bind to the enzymes <3.0nm from a single surface tryptophan. Free Aβ monomers bind to an enzyme, formulate a nucleus, initiate their aggregation and subsequently become entrapped and couple to the existing aggregated monomers, leading to an elongated fibril. Silver and gold nanoparticles reverse fibrillogenesis! They are surrounded by the amyloid peptide molecules in vivo to effectively deplete their concentration. This does not allow any 'lag' time, nor prevent the formation of critical nuclei for the initial association phase and, inevitably, prevent fibril initiation and elongation. This review focusses on the function and action of arginine metabolising enzymes with respect to the formation of senile plaques and amyloid peptide aggregation to facilitate more of an understanding of neurodegeneration in Alzheimer disease.

Keywords: Alzheimers disease; Arginine metabolizing enzymes; Fibrillogenesis; Inhibition; Mechanisms; Neuronal nitric oxide synthase; Peptidyl arginine deiminase.