Rab7a is required to degrade select blood-brain barrier junctional proteins after ischemic stroke.

Abstract

The integrity of adherens and tight junctions is critical for blood-brain barrier (BBB) function in the healthy brain. Disassembly of cell junctions due to degradation of adherens and tight junction-associated proteins leads to acute BBB dysfunction after ischemic stroke, but the mechanisms of this process are not fully understood. Using genetic studies in mice coupled with histopathological analysis of the brains after ischemic stroke, we demonstrate that endothelial cell deletion of Rab7a, a small GTPase crucial for protein degradation through the endolysosomal system, reduces acute BBB leakage and improves neuronal health in mice after ischemic stroke by reducing the degradation of select adherens and tight junction proteins, and preserving the structural morphology of tight junctions at both confocal and electron microscopy level. Two pro-inflammatory cytokines, TNFα and IL1β, that are known to trigger disruption of paracellular barrier properties in primary brain endothelial cells in vitro and are upregulated after ischemic stroke, contribute to Rab7a activation in primary mouse brain endothelial cells (BECs). In contrast, oxygen-glucose deprivation does not activate Rab7a in mouse BECs. Rab7a is, therefore, critical for degradation of select BEC junctional proteins during the acute increase in BBB permeability after ischemic stroke.