2. Academic Validation
  3. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

  • EBioMedicine. 2016 Jul;9:278-292. doi: 10.1016/j.ebiom.2016.06.002.
Florent Letronne 1,  Geoffroy Laumet 1,  Anne-Marie Ayral 1,  Julien Chapuis 1,  Florie Demiautte 1,  Mathias Laga 2,  Michel E Vandenberghe 3,  Nicolas Malmanche 1,  Florence Leroux 4,  Fanny Eysert 1,  Yoann Sottejeau 1,  Linda Chami 5,  Amandine Flaig 1,  Charlotte Bauer 5,  Pierre Dourlen 1,  Marie Lesaffre 6,  Charlotte Delay 1,  Ludovic Huot 7,  Julie Dumont 4,  Elisabeth Werkmeister 8,  Franck Lafont 8,  Tiago Mendes 1,  Franck Hansmannel 9,  Bart Dermaut 1,  Benoit Deprez 4,  Anne-Sophie Hérard 3,  Marc Dhenain 3,  Nicolas Souedet 3,  Florence Pasquier 10,  David Tulasne 6,  Claudine Berr 11,  Jean-Jacques Hauw 12,  Yves Lemoine 7,  Philippe Amouyel 13,  David Mann 14,  Rebecca Déprez 4,  Frédéric Checler 5,  David Hot 7,  Thierry Delzescaux 3,  Kris Gevaert 2,  Jean-Charles Lambert 15
Affiliations

Affiliations

  • 1 INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France.
  • 2 Department of Medical Protein Research, VIB, Ghent, Belgium; Department of Biochemistry, Ghent University, Ghent, Belgium.
  • 3 CEA, DSV, I2BM, MIRCen, Fontenay aux Roses, France; CNRS, UMR 9199, Fontenay aux Roses, France.
  • 4 Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France; INSERM U1177, Drugs and Molecules for Living Systems, F5900 Lille, France.
  • 5 Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS, Laboratoire d'Excellence Distalz, Nice, France; Université de Nice-Sophia-Antipolis, Valbonne, France.
  • 6 Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France.
  • 7 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.
  • 8 Institut Pasteur de Lille, F59000 Lille, France.
  • 9 INSERM, U954, Vandoeuvre-lès-Nancy, France; Department of Hepato-Gastroenterology, University Hospital of Nancy, Université Henri Poincaré 1, Vandoeuvre-lès-Nancy, France.
  • 10 Univ. Lille, Inserm, U1171, - Degenerative & Vascular Cognitive Disorders, Laboratoire d'Excellence Distalz, F-59000 Lille, France; CHR&U, Lille, France.
  • 11 INSERM, U1061, Université de Montpellier I, Hôpital La Colombière, Montpellier, France.
  • 12 APHP-Raymond Escourolle Neuropathology Laboratory, la salpétrière Hospital, Paris, France.
  • 13 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.
  • 14 Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, UK.
  • 15 INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France; Institut Pasteur de Lille, F59000 Lille, France; Univ. Lille, F59000 Lille, France. Electronic address: [email protected].
PMID: 27333034 DOI: 10.1016/j.ebiom.2016.06.002
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.

Keywords

ADAM30; APP; Alzheimer; Amyloid; LTP; Metabolism.

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