The role of the L-arginine/nitric oxide pathway in the pathology of Alzheimer's disease.

摘要

beta-amyloid (Abeta) peptides play a major role in the pathogenesis of Alzheimer's disease (AD). In this study, novel electrochemical nanosensors were used to directly monitor changes in the functionality of the NO/L-arginine pathway in human endothelial and human neuronal cell cultures modeled posit AD-like pathology. Studies were also performed on human brain samples (hippocampal tissue) from persons clinically diagnosed with various stages of AD. The results of these studies indicate that although Abeta increases constitutive nitric oxide synthase (cNOS) expression, it reduces the cNOS production of bioavailable NO. Abeta causes a simultaneous increase in the cNOS production of neurotoxic superoxide (O2-) and peroxynitrite (ONOO -). The Abeta-mediated dysfunction of cNOS was shown to be time-, dose-, and fragment-dependent in nature. Evidence has been presented that the dysfunction of cNOS in Alzheimer's brain may be due to L-arginine depletion caused by deposition of Abeta. A supplementation of L-arginine was shown to improve the NO/ONOO- ratio, effectively reducing Abeta-mediated oxidative (O2-) and nitroxidative (ONOO- ) stress caused by dysfunctional cNOS.