Separation of presenilin function in amyloid β-peptide generation and endoproteolysis of Notch

Most of the genetically inherited Alzheimer's disease cases are caused by mutations in the presenilin genes, PS1 and PS2. PS mutations result in the enhanced production of the highly amyloidogenic 42/43 amino acid variant of amyloid beta-peptide (A beta). We have introduced arbitrary mutations at position 286 of P51, where a naturally occurring PS1 mutation has been described (L286V), Introduction of charged amino acids (L286E or L286R) resulted in an increase of A beta 42/43 production, which reached almost twice the level of the naturally occurring PS1 mutation. Although pathological A beta production was increased, endoproteolysis of Notch and nuclear transport of its cytoplasmic domain was significantly inhibited. These results demonstrate that the biological function of PS proteins in the endoproteolysis of beta-amyloid precursor protein and Notch can be separated.