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J. Biol. Chem., Vol. 282, Issue 25, 18197-18205, June 22, 2007

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Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies^*

Valérie Vingtdeux¹, Malika Hamdane, Anne Loyens, Patrick Gelé, Hervé Drobeck^¶, Séverine Bégard, Marie-Christine Galas, André Delacourte, Jean-Claude Beauvillain, Luc Buée, and Nicolas Sergeant²

From the INSERM, U837, Neurodegenerative Disorders and Neuronal Death, and the Facultéde Médecine, Institut de Médecine Prédictive et de Recherche Thérapeutique, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France and ^¶CNRS, UMR 8161, "Lille Institute of Biology," University of Lille 1, Pasteur Institute of Lille, 1, rue du Professeur Calmette, F-59021 Lille Cedex, France

Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by -secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. (2007) Neurobiol. Dis. 25, 686–696). Herein, we aimed to determine the cell compartment in which AICD accumulates. We show that APP-CTFs and AICD are present in multivesicular structures. Multivesicular bodies contain intraluminal vesicles (known as exosomes) when released in the extracellular space. We demonstrate that APP, APP-CTFs, and AICD are integrated and secreted within exosomes in differentiated neuroblastoma and primary neuronal culture cells. Together with recent data showing that amyloid- is also found in exosomes, our data show that multivesicular bodies are essential organelles for APP metabolism and that all APP metabolites can be secreted in the extracellular space.

Received for publication, October 6, 2006 , and in revised form, April 23, 2007.

^* This work was supported in part by INSERM, CNRS, the Institut de Médecine Prédictive et de Recherche Thérapeutique of University of Lille 2, and APO-PIS Contract LSHM-CT-2003-503330. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Recipient of a fellowship from Association France Alzheimer.

² To whom correspondence and reprint requests should be addressed: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Jean-Pierre Aubert Research Centre, 1, Place de Verdun, F-59045 Lille, France. Tel.: 33-320-622-071; Fax: 33-320-622-079; E-mail: sergeant{at}lille.inserm.fr.

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