Blood–spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice

Abstract

Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of bloodderived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1 G93A mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1 G93A mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1 G93A mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.amyotrophic lateral sclerosis | neurodegeneration T he blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) prevent entry of toxic circulating molecules and cells into the central nervous system (CNS) (1). Amyotrophic lateral sclerosis (ALS) is the most prominent adult motor-neuron disorder resulting in progressive motor-neuron loss in the spinal cord, brainstem, and motor cortex (2). Most ALS cases are sporadic (90%) whereas 10% are familial ALS. Over twenty independent studies in postmortem human tissue and cerebrospinal fluid (CSF) sampling from living ALS patients have established that the BBB and BSCB are damaged in familial and sporadic ALS, as reviewed elsewhere (1, 3). This BBB and BSCB disruption has been shown by spinal-cord and/or motor-cortex accumulation of different plasma proteins (e.g., IgG, fibrin, thrombin), erythrocytes, erythrocyte-derived hemoglobin and iron-containing hemosiderin, elevated CSF/serum albumin ratios, and diminished expression or degradation of the BSCB tight-junction proteins (1, 3-5). Deposition of hemoglobin-derived iron within the CNS has also been shown in ALS patients (3, 6, 7). Because human postmortem studies reflect, however, end-stage disease, it has remained unclear as to which stage of disease is enhanced by BSCB disruption. Longitudinal CSF or BSCB imaging studies have yet to be performed in living ALS patients (3) to clarify whether spinal-cord vascular dysfunction contr...

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

“…injurious pathways occurring peripherally at the neuromuscular junction and centrally at the cell body of the motor neuron [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Histopatholgy in the animal model reveals a disruption at the neuromuscular junction that appears first followed by a "dying back" of the axon [25].…”

Expression of the ALS-Causing Variant hSOD1G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model

“…Treatment of hSOD1 G93A mice at an early disease stage furthermore restored the blood-spinal cord barrier integrity, which delayed the onset of motor-neuron impairment and degeneration and clearly demonstrated the therapeutic potential of APC for ALS. 44 Since this protective potential of APC is mediated by a Rac1-dependent signaling in association with an early reduction of ROS, and considering that Rac1 signaling and the production of ROS is altered in hSOD1 G93A cells, further studies are needed to elucidate the role of Rac1 signaling in endothelial cells of the blood-spinal cord barrier as well as the molecular mechanism leading to the barrier breakdown in ALS. Taken together, previous data from independent groups as well as ours provide strong evidence that the endothelial damage and accordingly the breakdown of the blood-spinal cord barrier is one of the primary events in ALS and that the regeneration of the barrier integrity may be a future promising target.…”

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“…Recent studies have highlighted the fact that BSCB/BBB is altered in ALS and that repair of this barrier should be a focus of future treatment options [12][13][14][15][16][17][18][19]. and Occludin (Ocln) [24].…”

“…Moreover, the severity of ALS inversely correlates with gray matter perfusion, again suggesting that the pathology of ALS is closely associated with dissociation of neurovascular components [52]. Thus, impaired BBB/BSCB, evidenced by decreases in tight junction proteins [24,49], increases in abnormal infiltrates in the CSF [47,48], and increases in oxidative species [50,51] can impact and propagate motor neuron degeneration in ALS [11,17,18,22,39,45]. In light of such evidence, it is important to further explore the specific role of astrocytes within the neurovascular unit in development of beneficial treatments for ALS.…”