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

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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

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