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 PS1 is endoproteolytically cleaved into 27 kDa N- and 17 kDa C-terminal fragments, which are the principal PS1 species found in normal mammalian brain. To examine the influence of mutant PS1 on Aβ formation and deposition in brain, we mated mice expressing wild-type and mutant PS1 to mice expressing a murine amyloid precursor protein (APP) with a humanized Aβ domain and missense mutations linked to a Swedish familial Alzheimer’s disease kindred (APP.swe). In the brains of mice that co-express mutant PS1 and APP.swe, the ratio of Aβ1–42/43 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 Aβ peptides.