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J. Biol. Chem., Vol. 278, Issue 14, 12325-12334, April 4, 2003

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A Synthetic Peptide Ligand of Neural Cell Adhesion Molecule (NCAM), C3d, Promotes Neuritogenesis and Synaptogenesis and Modulates Presynaptic Function in Primary Cultures of Rat Hippocampal Neurons^*

Darya Kiryushko^§, Thomas Kofoed^¶, Galina Skladchikova, Arne Holm^¶, Vladimir Berezin, and Elisabeth Bock

From the  Protein Laboratory, Institute of Molecular Pathology, Panum Institute Bldg. 6.2, Blegdamsvej 3C, DK-2200, Copenhagen N, Denmark, the ^§ Laboratory of Biophysics and Bioelectronics, Dniepropetrovsk State University, Naukovii pr. 13, 49050, Dniepropetrovsk, Ukraine, and the ^¶ Chemistry Department, Royal Agricultural and Veterinary University, Thorvaldsensvej 40, 1871 Frederiksberg, Denmark

The neural cell adhesion molecule (NCAM) plays a key role in morphogenesis of the nervous system and in remodeling of neuronal connections accompanying regenerative and cognitive processes. Recently, a new synthetic ligand of NCAM, the C3-peptide, which binds to the NCAM IgI module, has been identified by means of combinatorial chemistry (Rønn, L. C. B, Olsen, M., Ostergaard, S., Kiselyov, V., Berezin, V., Mortensen, M. T., Lerche, M. H., Jensen, P. H., Soroka, V., Saffell, J. L., Doherty, P., Poulsen, F. M., Bock, E., Holm, A., and Saffells, J. L. (1999) Nat. Biotechnol. 17, 1000-1005). In vitro, the dendrimeric form of C3, termed C3d, disrupts NCAM-mediated cell adhesion, induces neurite outgrowth, and triggers intracellular signaling cascades similar to those activated by homophilic NCAM binding. The peptide may therefore be expected to regulate regeneration and synaptic plasticity. Here we demonstrate that in primary cultures of hippocampal neurons: 1) C3d induces a sustained neuritogenic response, the neuritogenic activity of the compound being dependent on the dose, starting time, and duration of peptide application; 2) the peptide triggers the neuritogenic response by forming an adhesive substratum necessary for NCAM-mediated neurite formation and elongation; 3) C3d promotes synapse formation; and 4) C3d modulates the presynaptic function, causing a transient increase of the function at low (2 and 5 µM) doses and a reduction when applied at a higher concentration (10 µM). The effect of the peptide is dependent on the activation of the fibroblast growth factor receptor. We suggest that C3d may constitute a useful lead for the development of compounds for treatment of various neurodegenerative disorders.

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