Abstract
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) pedigrees1–7. PS1 encodes an ubiquitously expressed, eight transmembrane protein1,8–11. PS1 is endoproteolytically processed to an amino-terminal derivative (∼27–28 kDa) and a carboxy-terminal derivative (∼17–18 kDa). These polypeptides accumulate to saturable levels in the brains of transgenic mice, independent of the expression of PS1 holoprotein12. 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 (∼40–50%) than the fragments derived from wild-type PS1. Moreover, the FAD-linked ΔE9 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.
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Lee, M., Borchelt, D., Kim, G. et al. Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med 3, 756–760 (1997). https://doi.org/10.1038/nm0797-756
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DOI: https://doi.org/10.1038/nm0797-756
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