Blood–spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis

• Published in: Acta neuropathologica 2013-01, Vol.125 (1), p.111-120
• Main Authors: Winkler, Ethan A., Sengillo, Jesse D., Sullivan, John S., Henkel, Jenny S., Appel, Stanley H., Zlokovic, Berislav V.
• Format: Article
• Language: English
• Subjects: Aged; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - blood; Amyotrophic Lateral Sclerosis - cerebrospinal fluid; Amyotrophic Lateral Sclerosis - physiopathology; Blood proteins; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - physiopathology; Brain stem; Capillary Permeability; Central nervous system; Cortex (motor); Deposits; Endothelial Cells - metabolism; Erythrocytes; Extravasation; Female; Fibrin; Genetic engineering; Hemoglobin; Humans; Immunoglobulin G; Male; Medicine; Medicine & Public Health; Middle Aged; Motor Neurons - cytology; Motor Neurons - pathology; Motor nuclei; Nervous system diseases; Neurodegenerative diseases; Neurosciences; Original Paper; Pathology; Pericytes; Pericytes - cytology; Pericytes - metabolism; Platelet-derived growth factor; Spinal cord; Spinal Cord - blood supply; Spinal Cord - physiopathology; Thrombin; Tight Junctions - metabolism; Tight Junctions - pathology
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-012-1039-8

The blood–brain barrier and blood–spinal cord barrier (BSCB) limit the entry of plasma components and erythrocytes into the central nervous system (CNS). Pericytes play a key role in maintaining blood–CNS barriers. The BSCB is damaged in patients with amyotrophic lateral sclerosis (ALS). Moreover, transgenic ALS rodents and pericyte-deficient mice develop BSCB disruption with erythrocyte extravasation preceding motor neuron dysfunction. Here, we studied whether BSCB disruption with erythrocyte extravasation and pericyte loss are present in human ALS. We show that 11 of 11 cervical cords from ALS patients, but 0 of 5 non-neurodegenerative disorders controls, possess perivascular deposits of erythrocyte-derived hemoglobin and hemosiderin typically 10–50 μm in diameter suggestive of erythrocyte extravasation. Immunostaining for CD235a, a specific marker for erythrocytes, confirmed sporadic erythrocyte extravasation in ALS, but not controls. Quantitative analysis revealed a 3.1-fold increase in perivascular hemoglobin deposits in ALS compared to controls showing hemoglobin confined within the vascular lumen, which correlated with 2.5-fold increase in hemosiderin deposits ( r  = 0.82, p