Metabolism of presenilin 1: Influence of presenilin 1 on amyloid precursor protein processing

To create model systems to examine presenilin 1 (PS1) metabolism in vivo, we generated transgenic mice expressing wild-type and A246E mutant human PS1. Our data indicate that both wild-type and mutant PS I is endoproteolytically cleaved into 27 kDa N- and 17 kDa C-terminal fragments, which are the principal PS 1 species found in normal mammalian brain. To examine the influence of mutant PS 1 on A beta formation and deposition in brain, we mated mice expressing wild-type and mutant PS 1 to mice expressing a murine amyloid precursor protein (APP) with a humanized A beta domain and missense mutations linked to a Swedish familial Alzheimer's disease kindred (APP.swe). In the brains of mice that co-express mutant PS 1 and APP.swe, the ratio of A beta 1-42/43 to 1-40 was elevated by 50% compared to mice expressing APP.swe alone or mice expressing APP.swe and wild-type PS1. These data suggest that mutations in PS1 may cause early onset Alzheimer's disease by enhancing the concentration of longer, and more amyloidogenic, 42 and 43 residue A beta peptides. (C) 1998 Elsevier Science Inc.