The Nogo protein, notorious for its ability to sabotage nerve regeneration, appears to also promote the neurodegeneration seen in multiple sclerosis, at least in mice. An advance online article published June 6 in Nature Neuroscience reports that both active and passive immunization against Nogo protects animals against a disease studied as a proxy for multiple sclerosis (MS).

Observers of Nogo first encountered it in the context of inhibiting neurite outgrowth once the nervous system has matured. This finding has made Nogo a target for researchers who want to promote regeneration of damaged nerves, particularly after spinal cord trauma (see ARF related news story, Schwab et al., 2004).

But Nogo, with its A, B, and C isoforms, now appears to be far more than a one-trick obstructionist. For example, recent results point to a complex role for Nogo B in the migration of cells during vascular remodeling (Acevedo et al., 2004).

In the present study, Claude Bernard and Tara Karnezis of Latrobe University in Bundoora, Australia, and collaborators at Stanford University hypothesized that Nogo might play a role in the cycles of neurodegeneration and recovery that mark MS. To test this, they injected myelin oligodendrocyte glycoprotein into mice to induce experimental autoimmune encephalomyelitis (EAE), a common mouse model of MS. Although MS and Alzheimer’s disease are quite different, they both involve widespread neurodegeneration along with inflammatory processes in the afflicted areas. In fact, while MS has long been viewed as primarily a demyelinating disease, its neurodegenerative component has drawn increasing interest in recent years. For its part, AD appears to feature a prominent, if understudied, white matter/oligodendroglial component that is beginning to be more heavily studied in AD (see, for example, Bartzokis, 2004; Blalock et al., 2004).

First author Karnezis and colleagues set out to interfere with Nogo function in mice before inducing EAE. Indeed, active immunization with a small Nogo A fragment (residues 623-640) had a prophylactic effect. It reduced behavioral deficits and pathological damage, including both axonal degeneration and the extent of inflammatory lesions. Similarly, passive immunization with anti-Nogo IGg antibodies also reduced clinical features of EAE, the scientists report. Moreover, they found that in Nogo A/B/C knockout mice, EAE began later and ran a milder course.

The authors suggest that the active immunization protocol used in this study caused a shift away from a generally pathogenic Th1 response to a protective Th2 response. (In MS, the immune response consists both of T helper (Th1)-mediated proinflammatory activity and a B-cell antibody response.) This included a reduction in the proinflammatory cytokine interferon-γ and increases in the antiinflammatory cytokines transforming growth factor β and interleukin-10. These results are of interest in the context of Aβ immunization, where the AN1792 trial appears to have generated a Th1 response rather than just the desired antibody response.

A further possible link between Nogo and Alzheimer’s disease is the p75 receptor (see ARF related news story). This neurotrophin receptor, which frequently transmits signals promoting cell death, counts Aβ among its ligands and appears to form functional complexes with the Nogo receptor (Dechant and Barde, 2002).—Hakon Heimer


  1. The idea that damage to axons might be prevented and/or repaired by augmenting the activity of myelin-derived inhibitors of neurite outgrowth is exciting. It opens the door to the development of new molecular targets. The contribution of an aberrant immune system has been the hallmark of several human diseases, such as systemic lupus erythematosus, autoimmune diabetes, myasthenia gravis, Alzheimer’s disease (AD), multiple sclerosis (MS), etc. Autoantibodies plague the host in a battle where the “good guys” end up doing more harm than good. This is especially true in cases where the autoantigen resembles an unrelated antigen through molecular mimicry or epitope spreading (intramolecular and intermolecular).

    Much excitement has arisen from the discovery of Nogo and its receptor, NgR. A quick literature search brings up several hundred publications on this topic since their discovery in 2000 and 2001, respectively. Nogo is an inhibitor of axonal outgrowth, and its receptor is widely expressed in the cells of the CNS. In this report, Karnezis et al. show that blocking the actions of Nogo A blunts clinical signs, demyelination, and axonal damage associated with experimental autoimmune encephalomyelitis (EAE), a model of MS. [It is interesting to note that Nogo B has a similar effect on PDGF-induced smooth muscle migration.] These workers suggestworkers suggest that Nogo A is an important determinant of the development of EAE, and that its blockade may help to maintain and/or restore the neuronal integrity of the CNS after autoimmune insult in diseases such as MS.

    First, the authors immunized EAE-susceptible mice with the CNS-specific Nogo (623-640) peptide and observed beneficial results by reducing the time of disease onset as well as the severity of the disease symptoms. Then they targeted Nogo A through vaccination of EAE mice and were able to suppress EAE. This effect may have occurred through the modulation of the auto-reactivity to MOG, which has been reported as a primary CNS-specific target antigen promoting primary demyelination, and which is highly auto-antigenic in MS.

    Therefore, antibodies against Nogo not only decrease the incidence and severity of EAE but also block disease progression and, hence, should be considered a potent therapeutic agent for EAE. Axon loss is an early and continuous feature of the MS pathological process. The presence of antimyelin antibodies in the serum has been suggested as a predictor of clinically defined MS after the first demyelinating event. In fact, anti-Nogo antibodies are present in patients with MS, but is more frequent and in greater amounts in individuals with mild disability status.

    Somewhere in the clinical plan, one will need to characterize 1) the antibody’s affinity and avidity, and 2) the integrity of the blood-brain barrier (BBB) of the patient. Immunologically targeting a single epitope or protein could be an exhaustive task when considering the extensive intra- and intermolecular epitope spreading reported in chronic EAE. Such extensive diversity and spreading not only suggests considerably broader autoimmune responses, but also hat the design for antigen-specific, "tolerizing" therapies may be difficult. Unfortunately, the diversity of autoimmune responses poses a huge challenge to the development of antigen-specific neutralizing therapies. Despite this, new approaches are certainly needed.

    The integrity of the BBB in the patient also deserves consideration to allow antibody passage into the CNS. Experimental models of CNS neurodegeneration typically studies whichuse pertussis toxin—the virulence factor of Bordella pertussis that causes the childhood disease whooping cough—to disrupt the integrity of the BBB and allow antibodies to penetrate into the CNS. (Interestingly, group B streptococcal infection can also thwart the normal protective role of the BBB, leading to serious CNS infection.) It is important to note that other recent studies have determined that some human antibodies derived from patient serum can promote myelin repair in disease models of demyelination. In fact, in immunohistochemical studies, the labeling pattern of these antibodies suggests that they co-localize with anti-MOG antibody, a known marker of oligodendrocytes. Although this study did not comment on the BBB, one must concede that the BBB must be compromised for vascular-derived antibodies to have CNS effects.

    I believe that molecular mimicry and a dysfunctional BBB may be common factors in several CNS diseases including MS and AD. Overall, this is exciting data. For a single antibody regimen to be successful in treating MS, one must consider epitope expansion and the BBB.


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    . Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature. 2001 Jan 18;409(6818):341-6. PubMed.

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    . A new role for Nogo as a regulator of vascular remodeling. Nat Med. 2004 Apr;10(4):382-8. PubMed.

    . Nogo domains and a Nogo receptor: implications for axon regeneration. Neuron. 2001 Apr;30(1):11-4. PubMed.

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    View all comments by Michael R D'Andrea

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News Citations

  1. Neutralizing Nogo Allows Spinal Cord to Rewire Correctly
  2. NGF—From Crystal Structure to Human Trials

Paper Citations

  1. . Nogo and axon regeneration. Curr Opin Neurobiol. 2004 Feb;14(1):118-24. PubMed.
  2. . A new role for Nogo as a regulator of vascular remodeling. Nat Med. 2004 Apr;10(4):382-8. PubMed.
  3. . Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer's disease. Neurobiol Aging. 2004 Jan;25(1):5-18; author reply 49-62. PubMed.
  4. . Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2173-8. PubMed.
  5. . The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system. Nat Neurosci. 2002 Nov;5(11):1131-6. PubMed.

Further Reading


  1. . Rapid induction of autoantibodies against Nogo-A and MOG in the absence of an encephalitogenic T cell response: implication for immunotherapeutic approaches in neurological diseases. FASEB J. 2003 Dec;17(15):2275-7. PubMed.
  2. . Modulation of axonal regeneration in neurodegenerative disease: focus on Nogo. J Mol Neurosci. 2002 Aug-Oct;19(1-2):117-21. PubMed.
  3. . Inter- and intracellular interactions of Nogo: new findings and hypothesis. J Neurochem. 2004 May;89(4):801-6. PubMed.
  4. . Regulation of Nogo and Nogo receptor during the development of the entorhino-hippocampal pathway and after adult hippocampal lesions. Mol Cell Neurosci. 2004 May;26(1):34-49. PubMed.

Primary Papers

  1. . The neurite outgrowth inhibitor Nogo A is involved in autoimmune-mediated demyelination. Nat Neurosci. 2004 Jul;7(7):736-44. PubMed.