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 facto r in chronic neurodegenerative diseases such as Alzheimer's disease, A polipoprotein-E (apoE) and amyloid-beta eta 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 level s of apolipoprotein-E were found to stimulate nitric oxide (NO) produc tion 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 pe ptides, with or without poly I:C treatments. Furthermore, the combinat ion of A beta plus apoE inhibited the increase in NO production induce d by apoE. Since Alzheimer's is strongly associated with the presence of an APOE4 allele, our study predicts a mechanism where apoE and A be ta regulate nitric oxide production in human brain. (C) 1997 Academic Press.