Hyperaccumulation of FAD-linked presenilin 1 variants in vivo.

Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes can cause Alzheimer's disease in affected members of the majority of early-onset familial Alzheimer's disease (FAD) pedigrees. PS1 encodes an ubiquitously expressed, eight transmembrane protein. PS1 is endoproteolytically processed to an amino-terminal derivative (approximately 27-28 kDa) and a carboxy-terminal derivative (approximately 17-18 kDa). These polypeptides accumulate to saturable levels in the brains of transgenic mice, independent of the expression of PS1 holoprotein. We now document that, in the brains of transgenic mice, the absolute amounts of accumulated N- and C-terminal derivatives generated from the FAD-linked PS1 variants in which Glu replaces Ala at codon 246 (A246E) or Leu replaces Met at codon 146 (M146L) accumulate to a significantly higher degree (approximately 40-50%) than the fragments derived from wild-type PS1. Moreover, the FAD-linked deltaE9 PS1 variant, a polypeptide that is not subject to endoproteolytic cleavage in vivo, also accumulates in greater amounts than the fragments generated from wild-type human PS1. Thus, the metabolism of PS1 variants linked to FAD is fundamentally different from that of wild-type PS1 in vivo.

Modulators of carcinogenesis.

For decades, it has been known that a number of different factors (e.g., species, metabolism, age, animal husbandry, diet) may exhibit a significant modulating effect on the process of carcinogenesis. Often, however, these modulators have been largely uncontrolled and thus have made uncertain the results of many carcinogenicity bioassays. Fortunately, current research into molecular carcinogenesis is beginning to provide methods, not only to understand the molecular basis of known modulators of carcinogenesis, previously described only in empirical terms, but also to allow genetic modulation of carcinogenesis in experimental systems. An expanding body of knowledge regarding the role of oncogenes and tumor suppressor genes in neoplastic events is leading to a better understanding of carcinogenic mechanisms and points to the use of transgenic animal species in carcinogenicity bioassays. The transgenic animal provides methods to examine the molecular basis of carcinogenesis in experimental systems in addition to enhancing the sensitivity of carcinogen identification and the biological specificity of chemical risk extrapolation.