Neuroprotective effect of TNFalpha against the beta-amyloid neurotoxicity mediated by CDK5 kinase.
The tumor necrosis factor alpha (TNFalpha) plays a dual role in producing either neurodegeneration or neuroprotection in the central nervous system. Despite that TNFalpha 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 Abeta treatments. Since TNFalpha affects cdk5 activity, we investigated its possible protective role against the Abeta-induced neurodegeneration, as mediated by cdk5. TNFalpha pretreatments significantly reduced the hippocampal neuronal cell death induced by the effects of Abeta(42) peptide. In addition, this pretreatment reduced the increase in the activity of cdk5 induced by Abeta(42) in primary neurons. Next, we investigated the Alzheimer type phosphorylation of tau protein induced by Abeta(42). We observed that the pretreatment of neurons with TNFalpha reduces tau hyperphosphorylation. Taken together, these results define a novel neuroprotective effect of TNFalpha 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 Abeta peptide plays a key role in the development of Alzheimer etiopathogenesis.
Orellana
Daniel I
DI
Laboratory of Cellular, Molecular Biology and Neurosciences, Faculty of Sciences, Universidad de Chile; Las Encinas 3370, Nuñoa, Santiago, Chile.
Quintanilla
Rodrigo A
RA
Maccioni
Ricardo B
RB
D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5