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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 blood-derived 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.

SUBMITTER: Winkler EA 

PROVIDER: S-EPMC3964055 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Winkler Ethan A EA   Sengillo Jesse D JD   Sagare Abhay P AP   Zhao Zhen Z   Ma Qingyi Q   Zuniga Edward E   Wang Yaoming Y   Zhong Zhihui Z   Sullivan John S JS   Griffin John H JH   Cleveland Don W DW   Zlokovic Berislav V BV  

Proceedings of the National Academy of Sciences of the United States of America 20140303 11


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 neurodegenerativ  ...[more]

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