In vitro studies of interferon-alpha neurotoxicity (174.14)

Abstract

Abstract Elevated levels of interferon-alpha (IFNα) in the CNS is linked to cognitive dysfunction in patients with inflammatory CNS diseases such as HIV-associated dementia. Previous studies showed that IFNα treatment of neuronal cultures caused a dose dependent decrease in dendritic branching and length, mostly prevented after pre-treatment with IFNα neutralizing antibodies. To begin to evaluate the mechanism of decreased dendritic arborization, microtubule associate protein 2 (MAP2), cytoskeleton protein required for dendritic growth and stability in neurons, was looked at. IFNα was found to cause a decrease in total MAP2 protein levels in vitro as soon as 2 hrs after treatment that remained decreased through 48 hrs.. To begin to determine the signaling cascade leading up to effects on MAP2, the cell signaling pathway involving IFNα receptor (IFNAR) was evaluated to show STAT1 phosphorylation, an indicator for JAK-STAT cascade activation, peaks 2 hrs after IFNα stimulation. Both the MAPK/ERK and CREB pathways are being looked at due to their involvement in neuronal growth and STAT1 interaction. IFNα treatment appears to cause an increase ERK activity. The significance of these changese in transcription factor activity is yet to be determined. Our preliminary studies suggest that IFNα is in part acting through its receptor to reduce MAP2 expression in neurons. Determining the mechanism of IFNα neurotoxicity could lead to therapies for cognitive dysfunction during neuroinflammation.