Two classes of amyloid beta-protein precursors which differ by the presence of a serine protease inhibitor domain have been described. We have used synthetic oligonucleotide probes to investigate the tissue distribution and cellular localization of mRNAs encoding the two classes of amyloid beta-protein precursors. RNA blot analysis showed that transcripts encoding the protease inhibitor sequence are ubiquitously expressed in peripheral and central tissues. By contrast, transcripts lacking the protease inhibitor domain were only found in the central nervous system. By in situ hybridization on cerebral cortex and hippocampal formation both types of transcripts were present exclusively in nerve cells and they appeared to be produced by the same cells. A reduction in the transcript lacking the protease inhibitor domain was observed in frontal cortex from Alzheimer's disease patients. The present results indicate that there exists no correlation between the distribution of amyloid amyloid beta-protein precursor mRNAs and the tissue and cellular pathology of Alzheimer's disease; they also suggest that an overproduction of amyloid beta-protein precursor mRNA is unlikely to be responsible for amyloid beta-protein deposition in Alzheimer's disease.