Modulation of nitric oxide production in human macrophages by apolipoprotein-E and amyloid-beta peptide

Abstract

Induction of oxidative stress has been implicated as a causative factor in chronic neurodegenerative diseases such as Alzheimer's disease. Apolipoprotein-E (apoE) and amyloid-βeta peptide (Aβ) have been reported to alter the redox state of the brain. Using human monocyte derived macrophages as a model of brain microglia, physiological levels of apolipoprotein-E were found to stimulate nitric oxide (NO) production in polyinosinic:polycytidylic acid (poly I:C) primed cells. ApoE treatment released 68% more NO than cells treated with poly I:C alone and almost threefold more NO than unprimed cells. In contrast to mouse microglia, human cells failed to generate NO in response to Aβ peptides, with or without poly I:C treatments. Furthermore, the combination of Aβ plus apoE inhibited the increase in NO production induced by apoE. Since Alzheimer's is strongly associated with the presence of an APOE4 allele, our study predicts a mechanism where apoE and Aβ regulate nitric oxide production in human brain.