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

PNAS, 2014 · DOI: 10.1073/pnas.1401595111 · Published: March 3, 2014

Simple Explanation

The blood–spinal cord barrier (BSCB) prevents entry of toxic circulating molecules and cells into the central nervous system (CNS). 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. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1G93A mice at least in part through iron-dependent oxidant stress. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1G93A mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration.

Study Duration

From postnatal day 35 to clinical death

Participants

SOD1G93A mice, B6SJL littermates, SOD1WT mice

Evidence Level

Not specified

Key Findings

1
Early motor-neuron dysfunction and injury are proportional to the degree of BSCB disruption in SOD1G93A mice.
2
Early treatment with an activated protein C analog (5A-APC) restores BSCB integrity and delays the onset of motor-neuron impairment and degeneration.
3
Chelation of blood-derived iron and antioxidant treatment mitigate early motor-neuronal injury in SOD1G93A mice.

Research Summary

The study demonstrates that blood-spinal cord barrier (BSCB) breakdown contributes to early motor-neuron degeneration in ALS mice. Restoring BSCB integrity during an early disease phase retards the disease process in SOD1G93A mice. The findings suggest that BSCB disruption in patients with familial and/or sporadic ALS may contribute to early motor-neuron degeneration in humans.

Practical Implications

Therapeutic Target Identification

The BSCB is a potential therapeutic target for early intervention in ALS.

Drug Development

Activated protein C analogs and iron chelators may be beneficial in delaying ALS progression.

Translational Relevance

The findings are relevant to the corresponding disease mechanism in human ALS in which ALS-associated vascular pathology is associated.

Study Limitations

1
The study is conducted in ALS-model mice, and the direct applicability to human ALS needs further investigation.
2
The contribution of BBB damage to neurological disease in SOD1 transgenic rodents is presently unknown.
3
Future studies are needed using models with a chronic BBB/BSCB disruption independent of human SOD1 transgene expression.

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