A new concept in neurodegeneration: TNFalpha is a silencer of survival signals

The p55 receptor for the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) is best characterized by its ability to induce signals that trigger cell death. However, this is not the only way in which this TNF receptor kills neurons. A new view of neurodegeneration has recently emerged in which a TNF receptor induces death through the 'silencing of survival signals' (SOSS), such as phosphatidylinositol 3' kinase (PI3 kinase), that are activated by the insulin-like growth factor 1 receptor. This mechanism of intracellular crosstalk is the most pathophysiologically relevant action of TNFalpha in the brain and is applicable to a broad number of receptors that are localized on the same cell. Treatment of the more-devastating and costly neurodegenerative diseases of our time might be best promoted by increasing the efficacy of neuronal survival factors using new approaches aimed at inhibiting the SOSS.