Control of apolipoprotein E secretion by 25-hydroxycholesterol and proinflammatory cytokines in the human astrocytoma...

During the last few years the increased presence of proinflammatory cytokines and oxidation products in Alzheimer's disease (AD) has been largely described. Oxysterols, formed by hydroxylation of cholesterol, occur naturally in the brain and are increased in the serum of AD patients. Of these oxysterols, 25-hydroxycholesterol is the most potent regulator of gene transcription. It stimulates the synthesis of apolipoprotein E (apo E) in macrophages. Apo E plays a major role in the brain as a phospholipid and cholesterol carrier molecule in compensatory synaptogenesis. Cytokines might also be able to modulate apo E expression. Accordingly, this study examined the control of apo E secretion by several proinflammatory cytokines and oxysterols in the human astrocytoma cell line CCF-STTG1. A time-dependent stimulation of apo E secretion by 25-hydroxycholesterol was observed. Among several cytokines tested, only tumor necrosis factor (TNF)-alpha inhibited apo E secretion in basal conditions in CCF-STTG1 human astrocytoma cells. In the presence of 25-hydroxycholesterol, TNF-alpha reduced apo E secretion by 80%, while interleukins (IL) IL-1beta, IL-6, and IL-2 had no significant effects. In Alzheimer's disease, the increase in the concentrations of cytokines and the concomitant decrease of cholesterol concentration in the brain could contribute jointly to reduce apo E concentration, and in doing so accelerate neurodegeneration. Surprisingly, oxysterols would be able to limit this phenomenon.