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.
Export Options
About this article
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 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Is there a Possible Single Mediator in Modulating Neuroendocrine–thymus Interaction in Ageing?
Current Aging Science Oestradiol Signalling in the Hippocampus
Current Neuropharmacology Commentary: Histaminergic Drugs Could be Novel Targets for Neuroprotection in CNS Disorders
CNS & Neurological Disorders - Drug Targets Epigenetics and Sjogren’s Syndrome
Current Pharmaceutical Biotechnology Photoreduction of CO2 into hydrocarbons catalysed by ZnGa2O4/Ga2O3 heterojunction
Current Organic Chemistry Medicinal Chemistry of P2X Receptors: Agonists and Orthosteric Antagonists
Current Medicinal Chemistry Characterization of Fiber-Forming Peptides and Proteins by Means of Atomic Force Microscopy
Current Protein & Peptide Science Ubisol-AquaTM: Coenzyme Q10 Prevents Antiretroviral Toxic Neuropathy in an In Vitro Model
Current HIV Research Absorption Cooling: A Review of Lithium Bromide-Water Chiller Technologies
Recent Patents on Mechanical Engineering From Axonal Transport to Mitochondrial Trafficking: What Can We Learn from Manganese-Enhanced MRI Studies in Mouse Models of Alzheimers Disease?
Current Medical Imaging Clinical Use of Intracoronary Gene Transfer of Fibroblast Growth Factor for Coronary Artery Disease
Current Gene Therapy Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands
Current Topics in Medicinal Chemistry Multitarget Opioid/Non-opioid Ligands: A Potential Approach in Pain Management
Current Medicinal Chemistry Membrane Interactions of Oligomeric Alpha-Synuclein: Potential Role in Parkinsons Disease
Current Protein & Peptide Science Improving Medication Adherence in Chronic Pediatric Health Conditions: A Focus on ADHD in Youth
Current Pharmaceutical Design HIV Sex Risk Behaviors Among Heterosexual Methamphetamine Users: Literature Review from 2000 to Present
Current Drug Abuse Reviews Neuroprotection by NMDA Receptor Antagonists in a Variety of Neuropathologies
Current Drug Targets Training Children to Reduce Motion and Increase Success of MRI Scanning
Current Medical Imaging Life Cycle of Yeast Prions: Propagation Mediated by Amyloid Fibrils
Protein & Peptide Letters Oligonucleotides and G-quadruplex Stabilizers: Targeting Telomeres and Telomerase in Cancer Therapy
Current Pharmaceutical Design