Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway
Inflammation is a process that has been actively related with the onset of several neurodegenerative disorders including Alzheimer disease (AD). However, the precise implications of inflammatory response for neurodegeneration have not been elucidated. A current hypothesis considers that extracellular insults to neurons could trigger the production of inflammatory cytokines by astrocytes and microglia. These cytokines, namely, interleukin (IL)-1?, TNF?, and IL-6, could affect the normal behavior of neuronal cells. In the present study, we describe the effect of the administration at physiologic doses of one of these cytokines, IL-6, to hippocampal neurons, on the protein kinase pathways as well as on the tau phosphorylation patterns. IL-6-treated neurons exhibited an increase in the amount of anomalously hyperphosphorylated tau protein in epitopes dependent on proline-directed protein kinases (PDPKs). On the basis of our data, the observed increase of tau epitopes of Alzheimer type is explained by an increase of intraneuronal levels of p35 activator and in the activity of the protein kinase cdk5 in response to this cytokine. Further confirmation of cdk5 involvement in this process was based on the findings that inhibition of the kinase activity with butyrolactone-I prevents the appearance of tau of Alzheimer type in IL-6-treated neurons. Additional studies suggest that an increase of cdk5 activity could be mediated by a known signaling cascade described for IL-6 function, namely, the MAPK-p38 signaling pathway. Stimulation of the IL-6 pathway appears to increase the tau epitopes of Alzheimer type, as demonstrated in studies with specific inhibitors. These results support the findings of a pathologic role for IL-6 in the neuroinflammatory response as related with the pathogenesis of neuronal degeneration. © 2004 Elsevier Inc. All rights reserved.
|Título según WOS:||Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway|
|Título según SCOPUS:||Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway|
|Título de la Revista:||EXPERIMENTAL CELL RESEARCH|
|Editorial:||ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS|
|Fecha de publicación:||2004|
|Página de inicio:||245|