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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology
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Alzheimer Disease / physiopathology*
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Amyloid Precursor Protein Secretases
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Amyloid beta-Protein Precursor / deficiency
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Aspartic Acid Endopeptidases
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Brain / metabolism
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Case-Control Studies
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Caspase 3
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Caspases / metabolism
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Cell Death
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Cell Line
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Endopeptidases / metabolism*
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Enzyme Activation
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Female
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Humans
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Middle Aged
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Mutation
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Nerve Tissue Proteins / deficiency
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Peptide Fragments / metabolism
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Presenilin-1
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Presenilin-2
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Promoter Regions, Genetic
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Protein Structure, Tertiary
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Transcription, Genetic
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Transcriptional Activation
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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APLP2 protein, human
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Amyloid beta-Protein Precursor
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Membrane Proteins
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Nerve Tissue Proteins
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PSEN1 protein, human
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PSEN2 protein, human
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Peptide Fragments
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Presenilin-1
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Presenilin-2
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Tumor Suppressor Protein p53
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Amyloid Precursor Protein Secretases
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Endopeptidases
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CASP3 protein, human
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Caspase 3
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Caspases
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Aspartic Acid Endopeptidases
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BACE1 protein, human