title: ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease.
abstract: Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30(mut)) did not affect Aβ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aβ production, thereby contributing to Alzheimer's disease development.
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Letronne
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Laumet
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Ayral
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Chapuis
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Florie
authors.initials: F
authors.lastname: Demiautte
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Mathias
authors.initials: M
authors.lastname: Laga
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay aux Roses, France; CNRS, UMR 9199, Fontenay aux Roses, France.
authors.forename: Michel E
authors.initials: ME
authors.lastname: Vandenberghe
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Malmanche
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; INSERM U1177, Drugs and Molecules for Living Systems, F5900 Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Eysert
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Sottejeau
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS, Laboratoire d'Excellence Distalz, Nice, France; Université de Nice-Sophia-Antipolis, Valbonne, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Chami
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Flaig
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS, Laboratoire d'Excellence Distalz, Nice, France; Université de Nice-Sophia-Antipolis, Valbonne, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dourlen
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lesaffre
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Delay
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; Center for Infection and Immunity of Lille, CNRS UMR 8204, INSERM 1019, Lille, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Huot
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; INSERM U1177, Drugs and Molecules for Living Systems, F5900 Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dumont
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Werkmeister
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Lafont
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Tiago
authors.initials: T
authors.lastname: Mendes
authors.affiliation: INSERM, U954, Vandoeuvre-lès-Nancy, France; Department of Hepato-Gastroenterology, University Hospital of Nancy, Université Henri Poincaré 1, Vandoeuvre-lès-Nancy, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Hansmannel
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Dermaut
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; INSERM U1177, Drugs and Molecules for Living Systems, F5900 Lille, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay aux Roses, France; CNRS, UMR 9199, Fontenay aux Roses, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Hérard
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay aux Roses, France; CNRS, UMR 9199, Fontenay aux Roses, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Dhenain
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay aux Roses, France; CNRS, UMR 9199, Fontenay aux Roses, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Souedet
authors.affiliation: Univ. Lille, Inserm, U1171, - Degenerative & Vascular Cognitive Disorders, Laboratoire d'Excellence Distalz, F-59000 Lille, France; CHR&U, Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pasquier
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Tulasne
authors.affiliation: INSERM, U1061, Université de Montpellier I, Hôpital La Colombière, Montpellier, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Berr
authors.affiliation: APHP-Raymond Escourolle Neuropathology Laboratory, la salpétrière Hospital, Paris, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Hauw
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; Center for Infection and Immunity of Lille, CNRS UMR 8204, INSERM 1019, Lille, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Lemoine
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; CHR&U, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; INSERM U1177, Drugs and Molecules for Living Systems, F5900 Lille, France.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Déprez
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS, Laboratoire d'Excellence Distalz, Nice, France; Université de Nice-Sophia-Antipolis, Valbonne, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.affiliation: Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; Center for Infection and Immunity of Lille, CNRS UMR 8204, INSERM 1019, Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Hot
authors.affiliation: CEA, DSV, I2BM, MIRCen, Fontenay aux Roses, France; CNRS, UMR 9199, Fontenay aux Roses, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Delzescaux
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France. Electronic address: jean-charles.lambert@pasteur-lille.fr.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002402:Cathepsin D / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D018408:Patch-Clamp Techniques; D010436:Pepstatins / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018942:Macrolides; D010436:Pepstatins; D034741:RNA, Small Interfering; C057620:bafilomycin A; D002402:Cathepsin D; D051722:ADAM Proteins; C122190:ADAM30 protein, human; C031375:pepstatin
keywords: ADAM30; APP; Alzheimer; Amyloid; LTP; Metabolism