The tumor necrosis factor alpha (TNFα) plays a dual role in producing either neurodegeneration or neuroprotection in the central nervous system. Despite that TNFα 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 Aβ treatments. Since TNFα affects cdk5 activity, we investigated its possible protective role against the Aβ-induced neurodegeneration, as mediated by cdk5. TNFα pretreatments significantly reduced the hippocampal neuronal cell death induced by the effects of Aβ42 peptide. In addition, this pretreatment reduced the increase in the activity of cdk5 induced by Aβ42 in primary neurons. Next, we investigated the Alzheimer type phosphorylation of tau protein induced by Aβ42. We observed that the pretreatment of neurons with TNFα reduces tau hyperphosphorylation. Taken together, these results define a novel neuroprotective effect of TNFα 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 Aβ peptide plays a key role in the development of Alzheimer etiopathogenesis.
