Transgenic mouse lines were generated that expressed a 2-kb amyloid precursor protein (APP) promoter/beta-galactosidase reporter gene construction. In brain, hippocampal pyramidal neurons, neurons in the deeper layers of cerebral cortex, and neurons in several thalamic nuclei were heavily labeled by beta-galactosidase histochemistry. In general, molecular layers and white matter regions did not express the reporter gene. When compared with in situ hybridization for endogenous murine APP RNA, the striatum and outer layers of cerebral cortex had little reporter expression. Thus, the match between reporter expression and endogenous APP expression in brain was not perfect. A similar mismatch between the relative expression of the reporter gene and endogenous APP RNA distribution was found in homogenates from several organs. Although prior work in transgenic mice found similar mismatches in reporter gene distribution, none had tested the APP promoter construct in response to neuronal injury. Kainic acid injections successfully increased murine APP expression in the transgenic mice, but had no effect on the reporter gene expression. Based on these data and those collected by others, we conclude that the 2-kb region upstream of the APP transcription initiation site contains some elements responsible for the tissue-specific expression of this gene, but does not contain all the cis-acting elements sufficient for either the differential tissue distribution of this gene or the regulation of this gene subsequent to neural damage.