The beta-amyloid precursor protein (APP) is a membrane-bound glycoprotein which has been proposed to play a role both as a growth factor and a mediator of cell adhesion. Using the Neuro-2A neuroblastoma cell line, we have investigated the capacity of APP to mediate neural cell adhesion. The cells express the protein at a high level, the immunohistochemical staining pattern at the level of the membrane having a punctate pattern. Fab' fragments of antibodies to the extracellular portion of the molecule were found to inhibit cell binding to a collagen substrate, but not to laminin, fibronectin, or poly-l-lysine. Fab' fragments of antibodies to the nerve cell adhesion molecule N-CAM also inhibited binding of Neuro-2A cells specifically to collagen. This inhibition of cell-surface binding was accompanied by a repression of neurite outgrowth in differentiating cells in the presence of antibodies. APP antibodies also inhibited neuron-neuron and neuron-glial binding, but not glial-glial cell adhesion. These data suggest that the APP, which is expressed primarily on differentiated neuronal cells, may play a role in the mediation of both cell-cell and cell-substrate adhesion.