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

• In glial cells under an acute inflammatory stimulus lead to a significant increase of HIF-1 mRNA expression.
• In glial cells MAPK signalling is involved in HIF-1α mRNA expression.
• In the APP/PS1 experimental model of familial Alzheimer's disease, HIF-1α mRNA expression was not affected.

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-1α (HIF-1α), the key transcription factor regulating the expression of hypoxia-inducible genes, during glial activation is less known. Thus, we examined the significance of HIF-1α in three experimental models: first in an acute model of inflammation induced by pro-inflammatory cytokines TNF-α, IL-1β and IFN-γ; 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-α, IL-1β and IFN-γ, mRNA expression levels of HIF-1α 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-1α regulation. In addition, we observed that HIF-1α 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-1α mRNA in APP/PS1 mice during the course of the study (3–12 months of age). Thus, we demonstrated that HIF-1α 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, HIF-1α is not involved in neuronal apoptosis after PI3K/AKT inhibition.