Altered Blood-Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis.

For peripherally administered drugs to reach the central nervous system (CNS) and treat amyotrophic lateral sclerosis (ALS), they must cross the blood-brain barrier (BBB). As mounting evidence suggests that the ultrastructure of the BBB is altered in individuals with ALS and in animal models of ALS (e.g., SOD1 G93A mice), we characterized BBB transporter expression and function in transgenic C9orf72 BAC (C9-BAC) mice expressing a hexanucleotide repeat expansion, the most common genetic cause of ALS. Using an in situ transcardiac brain perfusion technique, we identified a 1.4-fold increase in 3 H-2-deoxy-D-glucose transport across the BBB in C9-BAC transgenic (C9) mice, relative to wild-type (WT) mice, which was associated with a 1.3-fold increase in brain microvascular glucose transporter 1 expression, while other general BBB permeability processes (passive diffusion, efflux transporter function) remained unaffected. We also performed proteomic analysis on isolated brain microvascular endothelial cells, in which we noted a mild (14.3%) reduction in zonula occludens-1 abundance in C9 relative to WT mice. Functional enrichment analysis highlighted trends in changes to various BBB transporters and cellular metabolism. To our knowledge, this is the first study to demonstrate altered BBB function in a C9orf72 repeat expansion model of ALS, which has implications on how therapeutics may access the brain in this mouse model.