Neuroprotective effect of TNFα against the β-amyloid neurotoxicity mediated by CDK5 kinase

The tumor necrosis factor alpha (TNF alpha) plays a dual role in producing either neurodegeneration or neuroprotection in the central nervous system. Despite that TNFa was initially described as a cell death inductor, neuroprotective effects against cell death induced by several neurotoxic insults have been reported. Tau hyperphosphorylation and neuronal death found in Alzheimer disease is mediated by deregulation of the cdk5/p35 complex induced by A beta treatments. Since TNF alpha affects cdk5 activity, we investigated its possible protective role against the A beta-induced neurodegeneration, as mediated by cdk5. TNF alpha pretreatmen'ts significantly reduced the hippocampal neuronal cell death induced by the effects of A beta(42) peptide. In addition, this pretreatment reduced the increase in the activity of cdk5 induced by A beta(42) in primary neurons. Next, we investigated the Alzheimer type phosphorylation of tau protein induced by A beta(42). We observed that the pretreatment of neurons with TNF alpha reduces tau hyperphosphorylation. Taken together, these results define a novel neuroprotective effect of TNFa in preventing neuronal cell death and cdk5-dependent tau hyperphosphorylation. This phenomenon, taken together with other previous findings, suggests that the inflammatory response due to A beta peptide plays a key role in the development of Alzheimer etiopathogenesis. (c) 2006 Elsevier B.V. All rights reserved.