Modulation of nitric oxide production in human macrophages by apolipoprotein-E and amyloid-beta peptide.
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-beta peptide (A beta) 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 A beta peptides, with or without poly I:C treatments. Furthermore, the combination of A beta 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 A beta regulate nitric oxide production in human brain.
Vitek
M P
MP
Division of Neurology, Duke University Medical Center, Durham, North Carolina 27710, USA. Vitek003@duke.edu
Snell
J
J
Dawson
H
H
Colton
C A
CA
D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics / Q000494:pharmacology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis*; D011070:Poly I-C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D011994:Recombinant Proteins; D009569:Nitric Oxide; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D011070:Poly I-C