Costimulatory effects of interferon-gamma and interleukin-1 beta or tumor necrosis factor alpha on the synthesis of a beta 1-40 and a beta 1-42 by human astrocytes

Chronic inflammation and astrocytosis are characteristic histopathological features of Alzheimer's Disease (AD). Astrocytes are one of the predominant cell types in the brain. In AD they are activated and produce inflammatory components such as complement components, acute phase proteins, and cytoki nes. In this study we analyzed the effect of cytokines on the production of amyloid beta (A beta) in the astrocytoma cell line U373 and in primary hum an astrocytes isolated postmortem from healthy aged persons as well as from patients with AD. Astrocytes did not produce A beta in the absence of stim uli or following stimulation with IL-1 beta, TNF alpha, IL-6, and TGF-beta1 . Neither did combinations of TNF alpha and IL-1 beta, IL-6 or TGF-beta1, o r the coadministration of IFN gamma and IL-6 or TGF-beta1 induce A beta pro duction. In contrast, pronounced production of A beta1-40 and A beta1-42 wa s observed when primary astrocytes or astrocytoma cells were stimulated wit h combinations of IFN gamma and TNF alpha or IFN gamma and IL-1 beta. Induc tion of AP production was accompanied by decreased glycosylation of APP as well as by increased secretion of APPs beta. Our results suggest that astro cytes may be an important source of A beta in the presence of certain combi nations of inflammatory cytokines. IFN gamma in combination with TNF alpha or IL-1 beta seems to trigger A beta production by supporting beta -secreta se cleavage of the immature APP molecule. (C) 2000 Academic Press.