The beta-amyloid precursor protein (APP) is involved in the degenerative and regenerative neural changes associated with aging and Alzheimer's disease. We studied the regulation of APP gene expression in a paradigm of degeneration and regeneration, the axotomized rat sciatic system. The sciatic nerves of rats were crushed and at intervals between 4 and 60 days, the affected dorsal root ganglia and spinal cord segments were processed for Northern analysis and in situ hybridization to evaluate various APP mRNA species. After nerve crush, dorsal root ganglia APP mRNA levels are increased for both APP695 (695 amino acids) and APPKPI (Kunitz protease inhibitor). Following reinnervation, APP695 returns to baseline but APPKPI remains elevated. In spinal cord there is a decrease of APP695, which returns to baseline following reinnervation. If regeneration is prevented, the initial phase of post-axotomy response for all APP forms persists for at least 60 days in both dorsal root ganglia and spinal cord. In situ hybridization confirms that the changes are referable to neurons. These findings indicate that neuron-target interactions are important in APP gene regulation; that the APP695 and APPKPI transcripts are differentially regulated following neuronal injury; and that different neuronal populations regulate APP expression in a cell-type specific manner.