Abstract
Amyloid β-peptide (Aβ), which plays a central role in Alzheimer Disease, is generated by presenilin-dependent and presenilin-independent γ-secretase cleavages of β-amyloid precursor protein (βAPP). We report that the presenilins (PS1 and PS2) also regulate p53-associated cell death Thus, we established that PS deficiency, catalytically inactive PS mutants, γ-secretase inhibitors and βAPP or APLP2 depletion reduced the expression and activity of p53, and lowered the transactivation of its promoter and mRNA levels. p53 expression was also reduced in the brains or βAPP-deficient mice or in brains where both PS had been invalidated by double conditional knock out. AICDC59 and AICDC50, the γ- and η- secretase-derived C-terminal fragments of βAPP, respectively, trigger the activation of caspase-3, p53-dependent cell death, and increase p53 activity and mRNA. Finally, HEK293 cells expressing PS1 harboring familial AD (FAD) mutations or FAD-affected brains, all display enhanced p53 activity and p53 expression. Our studies demonstrate that AICDs control p53 at a transcriptional level, in vitro and in vivo and unravel a still unknown function for presenilins.
Keywords: Presenilins, nicastrin, caspase-3, p53 expression, transcriptional activation
Current Alzheimer Research
Title: The γ /η-Secretase-Derived APP Intracellular Domain Fragments Regulate p53
Volume: 4 Issue: 4
Author(s): Frederic Checler, Claire Sunyach, Raphaelle Pardossi-Piquard, Jean Sevalle, Bruno Vincent, Toshitaka Kawarai, Nadege Girardot, Peter St George-Hyslop and Cristine Alves da Costa
Affiliation:
Keywords: Presenilins, nicastrin, caspase-3, p53 expression, transcriptional activation
Abstract: Amyloid β-peptide (Aβ), which plays a central role in Alzheimer Disease, is generated by presenilin-dependent and presenilin-independent γ-secretase cleavages of β-amyloid precursor protein (βAPP). We report that the presenilins (PS1 and PS2) also regulate p53-associated cell death Thus, we established that PS deficiency, catalytically inactive PS mutants, γ-secretase inhibitors and βAPP or APLP2 depletion reduced the expression and activity of p53, and lowered the transactivation of its promoter and mRNA levels. p53 expression was also reduced in the brains or βAPP-deficient mice or in brains where both PS had been invalidated by double conditional knock out. AICDC59 and AICDC50, the γ- and η- secretase-derived C-terminal fragments of βAPP, respectively, trigger the activation of caspase-3, p53-dependent cell death, and increase p53 activity and mRNA. Finally, HEK293 cells expressing PS1 harboring familial AD (FAD) mutations or FAD-affected brains, all display enhanced p53 activity and p53 expression. Our studies demonstrate that AICDs control p53 at a transcriptional level, in vitro and in vivo and unravel a still unknown function for presenilins.
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Cite this article as:
Checler Frederic, Sunyach Claire, Pardossi-Piquard Raphaelle, Sevalle Jean, Vincent Bruno, Kawarai Toshitaka, Girardot Nadege, George-Hyslop Peter St and da Costa Alves Cristine, The γ /η-Secretase-Derived APP Intracellular Domain Fragments Regulate p53, Current Alzheimer Research 2007; 4 (4) . https://dx.doi.org/10.2174/156720507781788945
DOI https://dx.doi.org/10.2174/156720507781788945 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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