QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, June 7, 2006, 26(23):6377-6385; doi:10.1523/JNEUROSCI.0651-06.2006

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alves da Costa, C. Articles by Checler, F. Search for Related Content PubMed PubMed Citation Articles by Alves da Costa, C. Articles by Checler, F. Pubmed/NCBI databases Medline Plus Health Information Alzheimer's Disease

 Previous Article  |  Next Article 

Neurobiology of Disease
Presenilin-Dependent -Secretase-Mediated Control of p53-Associated Cell Death in Alzheimer's Disease

Cristine Alves da Costa,¹ Claire Sunyach,^1 * Raphaelle Pardossi-Piquard,^1 * Jean Sévalle,¹ Bruno Vincent,¹ Nicole Boyer, ¹ Toshitaka Kawarai,² Nadège Girardot,³ Peter St. George-Hyslop,² and Frédéric Checler¹

¹Institute of Molecular and Cellular Pharmacology, Team Foundation for Medical Research, Coeducational Unit of Research 6097, National Center of Scientific Research/Nice-Sophia-Antipolis University, 06560 Valbonne, France, ²Center for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada, and ³National Institute of Health and Medical Research Unit 289, Pitié-Salpêtrière Hospital, Paris, France

Correspondence should be addressed to either of the following: Dr. Frédéric Checler, Institute of Molecular and Cellular Pharmacology, Coeducational Unit of Research 6097, National Center of Scientific Research/National Union of Autonomous Syndicates, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France, Email: checler{at}ipmc.cnrs.fr; or Dr. Cristine Alves da Costa, Institute of Molecular and Cellular Pharmacology, Coeducational Unit of Research 6097, National Center of Scientific Research/National Union of Autonomous Syndicates, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France, acosta{at}ipmc.cnrs.fr

Presenilins (PSs) are part of the -secretase complex that produces the amyloid -peptide (A) from its precursor [-amyloid precursor protein (APP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase A production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, -secretase inhibitors, and APP 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 APP-deficient mice. The - and -secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of APP 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.

Key words: presenilins; -secretase; AICD; apoptosis; p53; Alzheimer's disease

---

Received Feb. 14, 2006; revised April 27, 2006; accepted April 30, 2006.

Correspondence should be addressed to either of the following: Dr. Frédéric Checler, Institute of Molecular and Cellular Pharmacology, Coeducational Unit of Research 6097, National Center of Scientific Research/National Union of Autonomous Syndicates, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France, Email: checler{at}ipmc.cnrs.fr; or Dr. Cristine Alves da Costa, Institute of Molecular and Cellular Pharmacology, Coeducational Unit of Research 6097, National Center of Scientific Research/National Union of Autonomous Syndicates, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France, acosta{at}ipmc.cnrs.fr

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2006 26: i. [Full Text]  

This article has been cited by other articles:

				V. Buggia-Prevot, J. Sevalle, S. Rossner, and F. Checler NF{kappa}B-dependent Control of BACE1 Promoter Transactivation by A{beta}42 J. Biol. Chem., April 11, 2008; 283(15): 10037 - 10047. [Abstract] [Full Text] [PDF]

				P. Kienlen-Campard, B. Tasiaux, J. Van Hees, M. Li, S. Huysseune, T. Sato, J. Z. Fei, S. Aimoto, P. J. Courtoy, S. O. Smith, et al. Amyloidogenic Processing but Not Amyloid Precursor Protein (APP) Intracellular C-terminal Domain Production Requires a Precisely Oriented APP Dimer Assembled by Transmembrane GXXXG Motifs J. Biol. Chem., March 21, 2008; 283(12): 7733 - 7744. [Abstract] [Full Text] [PDF]

				J. Dunys, T. Kawarai, J. Sevalle, V. Dolcini, P. St. George-Hyslop, C. A. Da Costa, and F. Checler p53-dependent Aph-1 and Pen-2 Anti-apoptotic Phenotype Requires the Integrity of the {gamma}-Secretase Complex but Is Independent of Its Activity J. Biol. Chem., April 6, 2007; 282(14): 10516 - 10525. [Abstract] [Full Text] [PDF]

				Y. Li, A. Grupe, C. Rowland, P. Nowotny, J. S.K. Kauwe, S. Smemo, A. Hinrichs, K. Tacey, T. A. Toombs, S. Kwok, et al. DAPK1 variants are associated with Alzheimer's disease and allele-specific expression Hum. Mol. Genet., September 1, 2006; 15(17): 2560 - 2568. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help