HYPERACCUMULATION OF FAD-LINKED PRESENILIN-1 VARIANTS IN-VIVO

Mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes can c ause Alzheimer's disease in affected members of the majority of early- onset familiar Alzheimer's disease (FAD) pedigrees(1-7). PS1 encodes a n ubiquitously expressed, eight transmembrane protein(1,8-11). PS1 is endoproteolytically processed to an aminoterminal derivative (similar to 27-28 kDa) and a carboxy-terminal derivative (similar to 17-18 kDa) . These polypeptides accumulate to saturable levels in the brains of t ransgenic mice, independent of the expression of PS1 holoprotein(12). We now document that, in the brains of transgenic mice, the absolute a mounts 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 significant ly higher degree (similar to 40-50%) than the fragments derived from w ild-type PS1. Moreover, the FAD-linked Delta E9 PS1 variant, a polypep tide that is not subject to endoproteolytic cleavage in vivo, also acc umulates in greater amounts than the fragments generated from wild-typ e human PS1. Thus, the metabolism of PS1 variants linked to FAD is fun damentally different from that of wild-type PS1 in vivo.