Presenilin-dependent γ-secretase-mediated control of p53-associated cell death in Alzheimer's disease

Presenilins ( PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide ( A beta) from its precursor [ beta-amyloid precursor protein ( beta APP)]. Mutations in PS that cause familial Alzheimer's disease ( FAD) increase A beta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and beta APP or amyloid precursor protein-like protein 2 ( APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNA expression. p53 expression also is diminished in the brains of PS- or beta APP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain ( AICD) fragments ( AICDC59 and AICDC50, respectively) of beta APP trigger p53-dependent cell death and increase p53 activity and mRNA. Finally, PS1 mutations enhance p53 activity in human embryonic kidney 293 cells and p53 expression in FAD-affected brains. Thus our study shows that AICDs control p53 at a transcriptional level, in vitro and in vivo, and that FAD mutations increase p53 expression and activity in cells and human brains.