Zhong Z, Deane R, Ali Z, Parisi M, Shapovalov Y, O'Banion MK, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat Neurosci. 2008 Apr;11(4):420-2. PubMed.

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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 SOD1 is expressed at very high levels in brain endothelial cells (our unpublished gene profiling data), up to twice the level of other brain cell types, and they may be preferentially vulnerable to injury in SOD1 mutants for this reason.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:

    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA. The classical complement cascade mediates CNS synapse elimination. Cell. 2007 Dec 14;131(6):1164-78. PubMed.

    Lobsiger CS, Boillée S, Cleveland DW. 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.

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

    View all comments by Ben Barres

  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.

    References:

    Garbuzova-Davis S, Haller E, Saporta S, Kolomey I, Nicosia SV, Sanberg PR. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res. 2007 Jul 9;1157:126-37. PubMed.

    View all comments by Svitlana Garbuzova-Davis

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