Vascular profiling of the spinal cord and cortex reveals region-specific endothelial dysfunction and fibroblast remodeling in human ALS.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. Increasing evidence suggests that neurovascular dysfunction contributes to ALS pathogenesis, but a comprehensive understanding of vascular cell alterations in the human central nervous system remains lacking. Here, to systematically characterize neurovascular changes in ALS, we curated single-nucleus transcriptomic datasets from human spinal cord and cortical tissues with a specific focus on vascular cell populations. Comparative analyses revealed substantial vascular perturbations in the spinal cord compared to the cortex. Among vascular-associated cell populations, endothelial cells and fibroblasts exhibited the most pronounced transcriptional alterations. Endothelial cells from ALS spinal cords displayed reduced blood-brain barrier integrity signatures and increased expression of inflammatory and stress-response programs, with the greatest changes manifested in capillary endothelial cells. In parallel, we generated a refined cellular atlas of spinal cord fibroblasts and identified three major fibroblast populations, including a distinct LAMA1^low perivascular fibroblast subtype. Fibroblast signatures were found to be consistently elevated in ALS across single-nucleus transcriptomic, bulk transcriptomic, and experimental validation datasets. Together, our findings establish a region-resolved view of neurovascular alternations in human ALS, which is characterized by endothelial barrier dysfunction and disease-associated remodeling of specialized perivascular fibroblasts. These findings broaden the cellular framework of ALS pathogenesis beyond neuronal and glial alterations and highlight the neurovascular niche as an integral component of human ALS disease biology.