Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P‐Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1‐linked amyotrophic lateral sclerosis. Issue 8 (9th May 2016)

• Record Type: Journal Article
• Authors: Qosa, Hisham; Lichter, Jessica; Sarlo, Mark; Markandaiah, Shashirekha S.; McAvoy, Kevin; Richard, Jean‐Philippe; Jablonski, Michael R.; Maragakis, Nicholas J.; Pasinelli, Piera; Trotti, Davide
• Is Part Of: Glia. Volume 64:Issue 8(2016:Aug.)
• Page Start: 1298
• Page End: 1313
• Publication Date: 2016-05-09
• Subjects: amyotrophic lateral sclerosis -- endothelial cells -- blood–brain barrier -- P‐glycoprotein -- mutant SOD1; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23003
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract : The efficacy of drugs targeting the CNS is influenced by their limited brain access, which can lead to complete pharmacoresistance. Recently a tissue‐specific and selective upregulation of the multidrug efflux transporter ABCB1 or P‐glycoprotein (P‐gp) in the spinal cord of both patients and the mutant SOD1‐G93A mouse model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that prevalently kills motor neurons has been reported. Here, we extended the analysis of P‐gp expression in the SOD1‐G93A ALS mouse model and found that P‐gp upregulation was restricted to endothelial cells of the capillaries, while P‐gp expression was not detected in other cells of the spinal cord parenchyma such as astrocytes, oligodendrocytes, and neurons. Using both in vitro human and mouse models of the blood–brain barrier (BBB), we found that mutant SOD1 astrocytes were driving P‐gp upregulation in endothelial cells. In addition, a significant increase in reactive oxygen species production, Nrf2 and NFκB activation in endothelial cells exposed to mutant SOD1 astrocytes in both human and murine BBB models were observed. Most interestingly, astrocytes expressing FUS‐H517Q, a different familial ALS‐linked mutated gene, also drove NFκB‐dependent upregulation of P‐gp. However, the pathway was not dependent on oxidative stress but rather involved TNF‐α release. Overall, these findings indicated that nuclear translocation of NFκB was a converging mechanism used by endothelial cells of the BBB to upregulate P‐gp expression in mutant SOD1‐linked ALS and possibly other forms of familial ALS. GLIA 2016 GLIA 2016;64:1298–1313 Main Points: ALS‐linked mutant SOD1 astrocytes increase endothelial P‐glycoprotein expression and activity via oxidative stress Mutant FUS astrocytes upregulate endothelial P‐glycoprotein via TNF‐α release Pathways of upregulation converge on NFκB activation in endothelial cells