title: Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies.
abstract: 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 gamma-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-beta 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.
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vingtdeux
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Malika
authors.initials: M
authors.lastname: Hamdane
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Anne
authors.initials: A
authors.lastname: Loyens
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gelé
authors.affiliation: 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.
authors.forename: Hervé
authors.initials: H
authors.lastname: Drobeck
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Séverine
authors.initials: S
authors.lastname: Bégard
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Galas
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: André
authors.initials: A
authors.lastname: Delacourte
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beauvillain
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: INSERM, U837, Neurodegenerative Disorders and Neuronal Death, Centre de Recherches Jean-Pierre Aubert, Université Lille 2, Place de Verdun, F-59045 Lille, France; 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. Electronic address: sergeant@lille.inserm.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000196:embryology; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008954:Models, Biological; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D015388:Organelles / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000682:Amyloid; D004791:Enzyme Inhibitors; D018942:Macrolides; C040929:bafilomycin A1