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
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