Recently, new genetic linkages have been identified for early-onset familial Alzheimer's disease (AD). Mutations have been found in the presenilin (PS)-1 (S182) gene on chromosome 14 and the PS-2 (STM2/E5-a) gene on chromosome 1. We have investigated the distribution of gene expression of both presenilins in normal rat brain, and in human control and AD cases using in situ hybridization histochemistry. In normal rat brain, intense PS-1 mRNA expression was observed predominantly in neurons, particularly hippocampal pyramidal and dentate granular neurons and cerebellar Purkinje and granular neurons. The distribution of intensely expressing PS-2 mRNA cells was similar to that of PS-1, but additional groups in the brain stem and cortex were identified. Faint but significant mRNA expression of both PS genes was detected in white matter. In control human cases, the same neuronal cell types as seen in rat brain expressed both PS mRNAs in the hippocampus and cerebellum. In AD cases, the expression of both mRNAs was markedly decreased in the hippocampus but not in the cerebellum. In addition, PS-2 hybridization showed increased mRNA expression in astrocyte-like cells in affected areas of AD cases. The present data indicate that the PS genes may play important roles in specific neurons in normal brain, and that the decreased expression in neurons in sporadic AD brain may bear some relationship to the pathogenesis.