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

EBioMedicine

Jean-Jacques Hauw¹  Anne-Sophie Hérard²  Nicolas Souedet²  Michel E. Vandenberghe²  Thierry Delzescaux²  Marc Dhenain²  Kris Gevaert³  Mathias Laga³  Claudine Berr⁴  Tiago Mendes⁵  Pierre Dourlen⁵  Jean-Charles Lambert⁵  Bart Dermaut⁵  Geoffroy Laumet⁵  Nicolas Malmanche⁵  Amandine Flaig⁵  Florent Letronne⁵  Charlotte Delay⁵  Anne-Marie Ayral⁵  Fanny Eysert⁵  Julien Chapuis⁵  Philippe Amouyel⁵  Florie Demiautte⁵  Yoann Sottejeau⁵  Franck Hansmannel⁶  Benoit Deprez⁷  Julie Dumont⁷  Rebecca Déprez⁷  Ludovic Huot⁷  Elisabeth Werkmeister⁷  David Hot⁷  Yves Lemoine⁷  Florence Leroux⁷  Franck Lafont⁷  Frédéric Checler⁸  Charlotte Bauer⁸  Linda Chami⁸  David Mann⁹  Marie Lesaffre^1,10  David Tulasne^1,10  Florence Pasquier^1,11 

[1] APHP-Raymond Escourolle Neuropathology Laboratory, la salpétrière Hospital, Paris, France;CEA, DSV, I2BM, MIRCen, Fontenay aux Roses, France;Department of Medical Protein Research, VIB, Ghent, Belgium;INSERM, U1061, Université de Montpellier I, Hôpital La Colombière, Montpellier, France;INSERM, U1167, Laboratoire d'Excellence Distalz, F59000 Lille, France;INSERM, U954, Vandoeuvre-lès-Nancy, France;Institut Pasteur de Lille, F59000 Lille, France;Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS, Laboratoire d'Excellence Distalz, Nice, France;Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, UK;Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 – M3T – Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France;Univ. Lille, Inserm, U1171, - Degenerative & Vascular Cognitive Disorders, Laboratoire d'Excellence Distalz, F-59000 Lille, France;

关键词: Alzheimer;    APP;    ADAM30;    Amyloid;    Metabolism;    LTP;   

DOI  :  10.1016/j.ebiom.2016.06.002

来源: DOAJ

【 摘 要 】

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 (ADAM30mut) 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.

【 授权许可】

Unknown