Presenilin-dependent gamma-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 (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. W...

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Bibliographic Details
Published in:The Journal of neuroscience 2006-06, Vol.26 (23), p.6377-6385
Main Authors: Alves da Costa, Cristine, Sunyach, Claire, Pardossi-Piquard, Raphaelle, Sévalle, Jean, Vincent, Bruno, Boyer, Nicole, Kawarai, Toshitaka, Girardot, Nadège, St George-Hyslop, Peter, Checler, Frédéric
Format: Article
Language:English
Subjects:
Adult
Aged
Alzheimer Disease - genetics
Alzheimer Disease - pathology
Alzheimer Disease - physiopathology
Amyloid beta-Protein Precursor - deficiency
Amyloid beta-Protein Precursor - genetics
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Biochemistry, Molecular Biology
Brain - metabolism
Case-Control Studies
Caspase 3
Caspases - metabolism
Cell Death
Cell Line
Endopeptidases - metabolism
Enzyme Activation
Female
Humans
Life Sciences
Male
Membrane Proteins - genetics
Membrane Proteins - metabolism
Middle Aged
Mutation
Nerve Tissue Proteins - deficiency
Peptide Fragments - metabolism
Presenilin-1
Presenilin-2
Promoter Regions, Genetic
Protein Structure, Tertiary
Transcription, Genetic
Transcriptional Activation
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Description
Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0651-06.2006