Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models

De Lemos ML; de la Torre, AV; Petrov, D; Brox S; Folch, J; Pallas, M.; Lazarowski A; Beas-Zarate, C; Auladell, C; Camins, A

Keywords: apoptosis, c-jun, Alzheimer's, APP/PS1, HIF-1 alpha


The neuroinflammatory process is thought to contribute to the progression of neurological disorders and brain pathologies. The release of pro-inflammatory cytokines and chemokines by activated glial cells, astrocytes and microglia plays an important role in this process. However, the role of hypoxia-inducible factor-1 alpha (HIF-1 alpha), the key transcription factor regulating the expression of hypoxia-inducible genes, during glial activation is less known. Thus, we examined the significance of HIF-1 alpha in three experimental models: first in an acute model of inflammation induced by pro-inflammatory cytokines TNF-alpha, IL-1 beta and IFN-gamma; secondly, in a chronic model of inflammation using an APPswe/PS1dE9 (APP/PS1) transgenic mouse model of Alzheimer's disease and thirdly via the inhibition of the PI3K/AKT pathway in a model of neuronal apoptosis. During acute glial inflammation induced by in vitro administration of TNF-alpha, IL-1 beta and IFN-gamma, mRNA expression levels of HIF-1 alpha were significantly upregulated; however, this effect was blocked by SP600126, a pharmacological inhibitor of mitogen-activated protein kinases (MAPKs). These data suggest that MAPKs could be involved in HIF-1 alpha regulation. In addition, we observed that HIF-1 alpha is not involved in the neuronal apoptotic process mediated by PI3-kinase inhibition, which is regulated by c-Jun. Finally, we did not detect significant differences in the expression of HIF-1 alpha mRNA in APP/PS1 mice during the course of the study (3-12 months of age). Thus, we demonstrated that HIF-1 alpha has a prominent role in acute but not in chronic inflammatory processes, such as the one which occurs in the APP/PS1 experimental model of AD. Moreover, HIP-1 alpha is not involved in neuronal apoptosis after PI3K/AKT inhibition. (C) 2013 Elsevier Ltd. All rights reserved.

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Título según WOS: Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models
Volumen: 45
Número: 7
Fecha de publicación: 2013
Página de inicio: 1377
Página final: 1388
Idioma: English


Notas: ISI