If the inflammatory cytokine tumor necrosis factor α (TNF-α) is at work in Alzheimer's disease, it may not be relying on its well-described, directly apoptotic mechanism to cause problems, according to a report by Keith W. Kelley and his colleagues in the current issue of the Proceedingsof the National Academy of Sciences. These researcher report that TNF-α, in addition to causing cell death directly via its p55 receptor,can kill neurons indirectly through interference with insulin-like growth factor I (IGF-I), a hormone that promotes cell survival.

Challenging the orthodox models wherein TNF-α and IGF-I have unrelated and opposite effects on neuronal survival, Kelley and his colleagues demonstrate that small (as little as 10 pg/ml) quantities of TNF-α inhibit the ability of IGF-I to promote in vitro neuronal survival, specifically by inhibiting IGF-I-initiated signaling involving insulin receptor substrates I and II and phosphatidylinositol 3-kinase.

Yong Shen, of the Sun Health Institute, is impressed by the novelty of the findings and wants to know how TNF-α avoided going through its p55 receptor, for which it has a very high affinity. He also points out that the authors used cerebellar neurons from very young mice and says, "Whether this is directly related to human neurological diseases like Alzheimer's disease, which involve aged neurons in cortical areas, needs to be further investigated."—Hakon Heimer


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  1. . A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9879-84. PubMed.