Some forms of familial Alzheimer's disease are caused by mutations in the amyloid beta protein precursor (beta APP), and there is excellent evidence that these mutations foster amyloid deposition by increasing secretion of total amyloid beta protein (A beta) or the highly amyloidogenic A beta 1-42 form. These observations provide a powerful rationale for developing an animal model of AD by generating transgenic mice in which cerebral amyloid deposition is induced by A beta overproduction. To produce substantial A beta in vivo, we generated mice expressing the transgene of signal peptide and 99 residues of carboxyl-terminal fragment (CTF) of beta APP under control of the cytomegalovirus enhancer/chicken beta-actin promoter. The transgenic mRNA was detected in many tissues of these mice, but the levels of transgenic mRNA, CTF, and A beta did not correlate well indicating that tissue-specific posttranslational processing may play an important role in determining the amount of A beta that accumulates in various tissues. A beta was detected biochemically in brain, kidney, and pancreas with the largest amount present in pancreas. In transgenic plasma, there was a marked accumulation of human A beta 1-40 and A beta 1-42(43) to levels over 30-times those observed in normal human plasma. Thus, the transgenic mice produce and secrete considerable A beta. Despite this increase in A beta secretion and the elevated A beta in brain, immunohistochemistry revealed no consistent cerebral A beta deposition. In pancreas, however, intracellular A beta deposits were detected immunohistochemically in acinar cells and interstitial macrophages, some of which showed severe degeneration. In addition, examination of these cells by immunoelectron microscopy revealed many putative amyloid fibrils (7-12 nm) that were stained by anti-A beta antibodies. Overall, our findings indicate that tissue-specific posttranslational processing may play a pivotal role in A beta production and amyloid fibril formation in vivo. By carefully analyzing the changes that occur in the transgenic mice described here as compared to the transgenic line that has recently been shown to form extracellular amyloid plaques in brain, it may be possible to gain considerable insight into the factors that determine the location and amount of A beta that accumulates as amyloid.