Among cases of familial Alzheimer disease (AD), which represents a very small proportion of the total AD patients, several causal genes have been identified by recent molecular genetic studies. The investigations of the products of these genes are thought to be important for not only the pathogenesis of familial cases but probably also of the sporadic AD. Recently presenilin I (S182) on chromosome 14 was reported to be a disease gene of familial AD. In this study, we generated three rabbit polyclonal antibodies to presenilin I, i.e. to 15 amino acids of N-terminal (PS1N), C-terminal (PS1C), and in the loop structure (PS1L), by immunization with corresponding synthetic peptides. Using Western blotting and immunohistochemistry with these antibodies, we investigated the alterations of this protein in the fibroblasts from two FAD pedigrees, OS-2 and OS-3 mutated on the presenilin gene (96Val->Phe and 213Ile->Tyr respectively). The lysates from control and sporadic AD fibroblasts showed several polypeptide bands with anti-presenilin I antibodies. On the other hand, staining with PS1N showed that the fibroblast from OS-2 pedigree lacked two high molecular weight bands. Immunohistochemical staining of control fibroblasts with anti-presenilin I antibodies was observed along a reticular and network-like pattern in the cytoplasm. In contrast, the fibroblasts from OS-2 pedigree revealed uneven distribution of staining with PS1N. These data show for the first time abnormalities in the expression of presenilin I in fibroblasts due to mutation of 96Val->Phe in familial AD.