Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by the presence of amyloid plaques in the limbic and cerebral cortices of affected individuals. Ab is derived from the proteolytic cleavage of the amyloid precursor protein (APP). The APP family members are ubiquitously expressed type I integral membrane proteins that have relatively large extracellular domains [Gralle et al. (2006) J. Mol. Biol. 357:493-508] and short intracellular domains. In contrast to its known pathological role in the generation of Ab, the physiological functions of APP and its homologues remain poorly understood and the search for neuronal ligands or receptors that interact with the large ectodomain of APP has not been very fruitful. Claims that APP is involved in synapse formation, axonal and dendritic outgrowth and neuronal survival seem at least indirectly supported by recent findings suggesting that APP is part of a protein complex that has important functions in neuronal cell migration and synaptic transmission. With the goal of characterizing novel neuronal ligands for APP, we have used phage display of peptide libraries to identify peptides that bind to purified recombinant human sAPPa695 (the soluble ectodomain from the neuronal isoform of APP). Using this approach, we have isolated 5 cysteine-linked heptapeptides that bind to APP. Homology comparison with the human protein sequence databank revealed that 3 of the peptides are highly homologous to a neurite guidance protein and the other 2 peptides are homologous to the guidance protein receptor. These data suggest that APP is part of a neurite guidance complex. Moreover, we show that picomolar concentrations of sAPPa695 promote the survival of sympathetic neurons in culture in the absence of added growth factors. Interestingly, 3 of the peptides selected by phage display reverse this effect. Our findings open new avenues for the characterization of the physiological functions of APP and for its involvement in AD.