Costimulatory effects of interferon-γ and interleukin-1β or tumor necrosis factor α on the synthesis of aβ1-40 and aβ1-42 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 cytokines. 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 human astrocytes isolated postmortem from healthy aged persons as well as from patients with AD. Astrocytes did not produce A beta in the absence of stimuli 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, or the coadministration of IFN gamma and IL-6 or TGF-beta1 induce A beta production. In contrast, pronounced production of A beta1-40 and A beta1-42 was observed when primary astrocytes or astrocytoma cells were stimulated with combinations of IFN gamma and TNF alpha or IFN gamma and IL-1 beta. Induction of AP production was accompanied by decreased glycosylation of APP as well as by increased secretion of APPs beta. Our results suggest that astrocytes may be an important source of A beta in the presence of certain combinations of inflammatory cytokines. IFN gamma in combination with TNF alpha or IL-1 beta seems to trigger A beta production by supporting beta -secretase cleavage of the immature APP molecule. (C) 2000 Academic Press.