Loss of Blood-Spinal Cord Barrier Integrity Displays Regional Patterning in Amyotrophic Lateral Sclerosis
Sarah Waters1,3, Victor Dieriks2,3, Molly Swanson2,3, Natasha Grimsey1,3, Helen Murray2,3, Henry Waldvogel2,3, Maurice Curtis2,3, Richard Faull2,3, Mike Dragunow1,3 Emma Scotter1,3 1Department of Pharmacology and Clinical Pharmacology; 2Department of Anatomy and Medical Imaging; 3Centre for Brain Research, University of Auckland, Auckland, New Zealand
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by TDP-43 protein inclusions in the brain and spinal cord. TDP-43 deposition displays regional patterning across the spinal cord, with cervical and lumbar regions showing greatest deposition, and this corresponds with heavier motor neuron loss at these levels (1). The blood-spinal cord barrier (BSCB) is a specialised interface that restricts the entry of potentially neurotoxic blood components into the cord parenchyma, but the BSCB is compromised in ALS patients (2,3). Given the regional patterning of TDP-43 pathology and motor neuron loss in the ALS spinal cord, we examined their spatial correlation with BSCB leakage. Human spinal cord sections from cervical, thoracic and lumbar cord, from control (n = 5) and ALS (n = 13) cases, were immunostained for hemoglobin (vessel leakage), lectin (vessels), SMI-32 (motor neurons) and phosphorylated TDP-43. Spinal cord sections were imaged and analysed using a semi-automated pipeline designed in-house. pTDP-43 pathology and motor neuron loss were observed across the spinal cord, with heaviest motor neuron loss at the cervical level. Hemoglobin extravasation was striking in most ALS spinal cords, being seen in both grey and white matter, and most severe at thoracic levels T7-T9. We propose that BSCB leakage is transient; evolving and resolving first in the cervical and lumbar regions. Extensive hemoglobin leakage in the thoracic cord together with significant motor neuron loss suggests that BSCB compromise is either promoted by, or contributes to, neurotoxicity in ALS.
References 1. Brettschneider J, Arai K, Del Tredici K, Toledo JB, Robinson JL, Lee EB, et al. TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol. 2014 Sep;128(3):423-37. 2. Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 2013 Jan;125(1):111-20. 3. Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MC, Haller E, Frisina-Deyo A, Mirtyl S, et al. Impaired blood-brain/spinal cord barrier in ALS patients. Brain Res. 2012 Aug 21;1469:114-28.
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