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Excess glutamate secreted from astrocytes drives upregulation of P‐glycoprotein in endothelial cells in amyotrophic lateral sclerosis

Loqman A. Mohamed,S. Markandaiah,S. Bonanno,P. Pasinelli,D. Trotti

Published 2019 in Experimental Neurology

ABSTRACT

&NA; In amyotrophic lateral sclerosis (ALS), upregulation in expression and activity of the ABC transporter P‐glycoprotein (P‐gp) driven by disease advancement progressively reduces CNS penetration and efficacy of the ALS drug, riluzole. Post‐mortem spinal cord tissues from ALS patients revealed elevated P‐gp expression levels in endothelial cells of the blood‐spinal cord barrier compared to levels measured in control, non‐diseased individuals. We recently found that astrocytes expressing familial ALS‐linked SOD1 mutations regulate expression levels of P‐gp in endothelial cells, which also exhibit a concomitant, significant increase in reactive oxygen species production and NF&kgr;B nuclear translocation when exposed to mutant SOD1 astrocyte conditioned media. In this study, we found that glutamate, which is abnormally secreted by mutant SOD1 and sporadic ALS astrocytes, drives upregulation of P‐gp expression and activity levels in endothelial cells via activation of N‐Methyl‐D‐Aspartic acid (NMDA) receptors. Surprisingly, astrocyte‐secreted glutamate regulation of endothelial P‐gp levels is not a mechanism shared by all forms of ALS. C9orf72‐ALS astrocytes had no effect on endothelial cell P‐gp expression and did not display increased glutamate secretion. Utilizing an optimized in vitro human BBB model consisting of patient‐derived induced pluripotent stem cells, we showed that co‐culture of endothelial cells with patient‐derived astrocytes increased P‐gp expression levels and transport activity, which was significantly reduced when endothelial cells were incubated with the NMDAR antagonist, MK801. Overall, our findings unraveled a complex molecular interplay between astrocytes of different ALS genotypes and endothelial cells potentially occurring in disease that could differentially impact ALS prognosis and efficacy of pharmacotherapies.

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