title: Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease.
abstract: Presenilins (PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide (Abeta) from its precursor [beta-amyloid precursor protein (betaAPP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase Abeta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and betaAPP 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 betaAPP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of betaAPP 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.
authors.affiliation: Institute of Molecular and Cellular Pharmacology, Coeducational Unit of Research 6097, National Center of Scientific Research/Nice-Sophia-Antipolis University, 06560 Valbonne, France. acosta@ipmc.cnrs.fr
authors.forename: Cristine
authors.initials: C
authors.lastname: Alves da Costa
authors.forename: Claire
authors.initials: C
authors.lastname: Sunyach
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Pardossi-Piquard
authors.forename: Jean
authors.initials: J
authors.lastname: Sévalle
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincent
authors.forename: Nicole
authors.initials: N
authors.lastname: Boyer
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Nadège
authors.initials: N
authors.lastname: Girardot
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000172:deficiency; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; D016159:Tumor Suppressor Protein p53; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human