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The Journal of Neuroscience, July 18, 2007, 27(29):7663-7672; doi:10.1523/JNEUROSCI.5623-06.2007

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Neurobiology of Disease
The Membrane Attack Complex of the Complement System Is Essential for Rapid Wallerian Degeneration

Valeria Ramaglia,¹ Rosalind Helen Mary King,⁴ Michelle Nourallah,⁴ Ruud Wolterman,¹ Rosalein de Jonge,¹ Marja Ramkema,³ Miriam Ann Vigar,⁵ Sandra van der Wetering,⁶ Brian Paul Morgan,⁵ Dirk Troost,³ and Frank Baas^1,2

¹Neurogenetics Laboratory, ²Department of Neurology, and ³Department of Neuropathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, ⁴Department of Clinical Neurosciences, Royal Free and University College Medical School, London NW3 2PF, United Kingdom, ⁵Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom, and ⁶Pharming, 2300 AL Leiden, The Netherlands

Correspondence should be addressed to Dr. Frank Baas, University of Amsterdam, Academic Medical Center, Neurogenetics Laboratory, Meibergdreef 9, 1105 AZ Amsterdam Zuidoost, The Netherlands. Email: f.baas{at}amc.uva.nl

The complement (C) system plays an important role in myelin breakdown during Wallerian degeneration (WD). The pathway and mechanism involved are, however, not clear. In a crush injury model of the sciatic nerve, we show that C6, necessary for the assembly of the membrane attack complex (MAC), is essential for rapid WD. At 3 d after injury, pronounced WD occurred in wild-type animals, whereas the axons and myelin of C6-deficient animals appeared intact. Macrophage recruitment and activation was inhibited in C6-deficient rats. However, 7 d after injury, the distal part of the C6-deficient nerves appeared degraded. As a consequence of a delayed WD, more myelin breakdown products were present than in wild-type nerves. Reconstitution of the C6-deficient animals with C6 restored the wild-type phenotype. Treatment with rhC1INH (recombinant human complement 1 inhibitor) blocked deposition of activated C-cleaved products after injury. These experiments demonstrate that the classical pathway of the complement system is activated after acute nerve trauma and that the entire complement cascade, including MAC deposition, is essential for rapid WD and efficient clearance of myelin after acute peripheral nerve trauma.

Key words: Wallerian degeneration; crush injury; complement; macrophage; neurodegenerative disease; neuropathy

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Received Dec. 28, 2006; revised May 24, 2007; accepted May 26, 2007.

Correspondence should be addressed to Dr. Frank Baas, University of Amsterdam, Academic Medical Center, Neurogenetics Laboratory, Meibergdreef 9, 1105 AZ Amsterdam Zuidoost, The Netherlands. Email: f.baas{at}amc.uva.nl

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