Astrocytes Regulate Endothelial Cell Drug Efflux Pumps in ALS Models

The drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are expressed on endothelial cells of the blood brain barrier (BBB) and blocks entry of toxins into the central nervous system (CNS). However, they may also prevent entry of beneficial drugs. Both transporters are expressed at elevated levels in the spinal cord of ALS mice and in postmortem spinal cord from ALS patients, and a drug that blocks them enhances the effect of riluzole in ALS mice (see Dec 2014 news). A follow up study published in the May 9 Glia online by Davide Trotti and colleagues from Thomas Jefferson University in Philadelphia, PA,  sheds light on the mechanisms that regulate expression of these transporters in ALS. Co-culture experiments with human iPSCs reveal that astrocytes expressing SOD1 or FUS mutations drive an increase in P-gp expression on BBB endothelial cells in an NFkB-dependent manner. Interestingly, these two mutations exert this effect through distinct signaling cascades.

Primary Reference:
Qosa H, Lichter J, Sarlo M, Markandaiah SS, McAvoy K, Richard JP, Jablonski MR, Maragakis NJ, Pasinelli P, Trotti D. 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. Glia. 2016 Aug;64(8):1298-313. Epub 2016 May 9.[Pubmed].

astrocyte BBB disease-als nf-kb topic-preclinical
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