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J. Biol. Chem., Vol. 280, Issue 7, 5862-5869, February 18, 2005

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Overcoming the Inhibitors of Myelin with a Novel Neurotrophin Strategy^*

Gareth Williams, Emma-Jane Williams, Patrick Maison, Menelas N. Pangalos¶, Frank S. Walsh¶, and Patrick Doherty||

From the The Wolfson Centre for Age-related Diseases, King's College London, London SE1 1UL, United Kingdom and ^¶Discovery Research, Wyeth Research, Collegeville, Pennsylvania 19426

Myelin inhibitors activate a p75^NTR-dependent signaling cascade in neurons that not only inhibits axonal growth but also prevents neurotrophins (NT) from stimulating growth. Most intriguingly, in addition to Trk receptors, neurotrophins also bind to p75^NTR. We have designed a "mini-neurotrophin" called B_AG to activate TrkB in the absence of p75^NTR binding. We find that B_AG is as effective as the natural TrkB ligands (brain-derived neurotrophic factor (BDNF) and NT-4) at promoting neurite outgrowth from cerebellar neurons. Furthermore, the neurite outgrowth responses stimulated by BDNF and B_AG are inhibited by a common set of reagents, including the Trk receptor inhibitor K252a, as well as protein kinase A and phosphoinositide 3-kinase inhibitors. However, in contrast to BDNF, B_AG promotes growth in the presence of a myelin inhibitor or when antibodies directly activate the p75^NTR inhibitory pathway. On the basis of this observation, we postulated that the binding of BDNF to the p75^NTR might compromise the ability of BDNF to stimulate neurite outgrowth in an inhibitory environment. To test this, we used NGF, and an NGF-derived peptide, to compete for the BDNF/p75^NTR interaction; remarkably, in the presence of either agent, BDNF acquired the ability to promote neurite outgrowth in the presence of a myelin inhibitor. The data suggest that in an inhibitory environment, the BDNF/p75^NTR interaction compromises regeneration. Agents that activate Trk receptors in the absence of p75^NTR binding, or agents that inhibit neurotrophin/p75^NTR binding, might therefore be better therapeutic candidates than neurotrophins.

Received for publication, September 28, 2004 , and in revised form, November 12, 2004.

^* This work was supported in part by Wyeth, and the Biotechnology and Biological Sciences Research Council of Great Britain supported the work in the Doherty laboratory. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Medical Research Council of Great Britain.

^|| To whom correspondence should be addressed: The Wolfson Centre for Age-related Diseases, Kings College London, Hodgkin BLD, St Thomas' St., London SE1 1UL, UK. Tel.: 207-848-6811; Fax: 207-848-6816; E-mail: patrick.doherty{at}kcl.ac.uk.

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