A paper out March 16 in Nature Neuroscience from Berislav Zlokovic and colleagues at the University of Rochester in New York finds that mice expressing SOD1 mutations associated with inherited forms of amyotrophic lateral sclerosis (ALS) show vascular defects early in life, before motor neurons begin to degenerate. First author Zhihui Zhong and coworkers present evidence for a leaky blood-spinal cord barrier associated with microhemorrhages, neuroinflammation, reduced capillary density, and lowered blood flow. The researchers conclude that compromised circulation is an early event that could contribute to degeneration of motor neurons in these ALS models.

Previous work has shown breaches in the blood-brain barrier in symptomatic SOD1 mice with early or advanced disease (Garbuzova-Davis et al., 2007). In the new study, the effects show up presymptomatically, and get progressively worse with time. The appearance of vascular defects as early as two months of age precedes the onset of inflammation, and that then leads to further damage to the blood-brain barrier (BBB) as observed in people with ALS (Graves et al., 2004).

“Our study demonstrates that changes to the vasculature probably make an important contribution to the degeneration of large motor neurons in familial models of ALS,” the researchers conclude. The vascular changes, they showed, appeared to result from decreases in the expression of the tight junction proteins ZO-1, occludin and claudin-5 in endothelial cells that make up the BBB. “All of this evidence supports the idea that mutant-mediated damage to the vasculature contributes to initiating non-cell autonomous killing of motor neurons in inherited ALS,” they write.—Pat McCaffrey

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  1. The mechanism by which SOD1 leads to motor neuron death in ALS is of great interest; much controversy has surrounded which are the relevant cell type(s) in which mutant SOD1 exerts its deleterious effects. This is a very interesting study demonstrating early blood-brain barrier (BBB) defects in the SOD1 mutant mouse model of ALS prior to frank neurodegeneration. SOD1 is expressed at very high levels in brain endothelial cells (our unpublished gene profiling data), up to twice the level of other brain cell types, and they may be preferentially vulnerable to injury in SOD1 mutants for this reason. The blood-brain barrier breakdown is also increasingly implicated in Alzheimer disease, though it remains unclear whether such changes occur early in AD or late in AD.

    In the present paper the provocative observation is that these changes occur early. This is particularly interesting because of new (e.g., Stevens et al., 2007; Lobsiger et al., 2007) and old work (reviewed in McGeer et al., 2005) suggesting complement activation in neurodegenerative disease, including the mouse model of ALS and in human ALS. The blood-brain barrier leakage will thus enable high levels of complement proteins to enter the CNS, and these might contribute ultimately to triggering neuroinflammation. It will be of great interest in future studies to see if endothelial expression of mutant SOD1 and/or blood-brain barrier breakdown is required for motor neuron degeneration to occur, and whether prevention of BBB breakdown can lessen the motor neuron degeneration.

    References:

    . The classical complement cascade mediates CNS synapse elimination. Cell. 2007 Dec 14;131(6):1164-78. PubMed.

    . Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7319-26. PubMed.

    . Inflammation, the complement system and the diseases of aging. Neurobiol Aging. 2005 Dec;26 Suppl 1:94-7. PubMed.

  2. This is a thorough and important work, confirming and extending our original findings of dysfunction and structural damage, vascular leakage and edema, in the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) even in early-symptomatic G93A ALS mice (Garbuzova-Davis et al., 2007). The authors found BSCB damage in presymptomatic mice and in other ALS mouse models expressing different SOD mutations. Importantly, as we already know that inflammatory processes can alter the BBB, damage was noted in mice prior to the onset of inflammation. This also may have implications for other neurodegenerative diseases such as Alzheimer’s and Parkinson’s, where BBB damage has already been identified in patients. This finding, and our previous findings, may lead to revised pharmaceutical treatments for ALS, some of which assume a functional, intact BBB/BSCB. However, the article leaves open the questions of which disease mechanisms are affecting the BBB/BSCB and, our current focus, how the BBB/BSCB may be repaired.

    View all comments by Svitlana Garbuzova-Davis

References

Paper Citations

  1. . Evidence of compromised blood-spinal cord barrier in early and late symptomatic SOD1 mice modeling ALS. PLoS One. 2007;2(11):e1205. PubMed.
  2. . Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Dec;5(4):213-9. PubMed.

Further Reading

Primary Papers

  1. . ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci. 2008 Apr;11(4):420-2. PubMed.