Abstract

Significance The blood–spinal cord barrier (BSCB) is damaged in human ALS and rodents expressing ALS-associated superoxide dismutase mutations. The role of BSCB breakdown in disease pathogenesis remains, however, unclear. Early motor-neuron dysfunction and injury are now shown to be proportional to the degree of BSCB disruption, and early protection of the BSCB integrity with an activated protein C analog is found to delay onset of motor-neuron impairment and degeneration. Altogether, these findings in mice show that BSCB breakdown plays a role in early-stage disease pathogenesis and that restoring BSCB integrity retards the disease process. These findings are relevant to the corresponding disease mechanism in human ALS in which ALS-associated vascular pathology is associated.