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

Florent Letronne (1, 2) , Geoffroy Laumet (2) , Anne-Marie Ayral (2) , Julien Chapuis (2) , Florie Demiautte (2) , Mathias Laga (3, 4) , Michel Vandenberghe (5) , Nicolas Malmanche (2) , Florence Leroux (6) , Fanny Eysert (2) , Yoann Sottejeau (2) , Linda Chami (7) , Amandine Flaig (2) , Charlotte Bauer (7) , Pierre Dourlen (2) , Marie Lesaffre (8) , Charlotte Delay (2) , Ludovic Huot (9) , Julie Dumont (6) , Elisabeth Werkmeister (10) , Franck Lafont (9) , Tiago Mendes (2) , Franck Hansmannel (11, 12) , Bart Dermaut (2) , Benoit Deprez (6) , Anne-Sophie Herard (5) , Marc Dhenain (13, 5) , Nicolas Souedet (5) , Florence Pasquier (14) , David Tulasne (8) , Claudine Berr (15) , Jean-Jacques Hauw (16) , Yves Lemoine (9) , Philippe Amouyel (1, 2) , David Mann (17) , Rebecca Déprez (6) , Frédéric Checler (7) , David Hot (9) , Thierry Delzescaux (5) , Kris Gevaert (3, 4) , Jean-Charles Lambert (2)

1 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
2 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
3 VIB - Vlaams Instituut voor Biotechnologie [Ghent, Belgique]
4 UGENT - Universiteit Gent = Ghent University
5 LMN - Laboratoire des Maladies Neurodégénératives - UMR 9199
6 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177
7 IPMC - Institut de pharmacologie moléculaire et cellulaire
8 M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161
9 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
10 Institut Pasteur de Lille
11 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
12 Service d'Hépato-gastro-entérologie [CHRU Nancy]
13 UGRA / SETA - CEA [Fontenay-aux-Roses]
14 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
15 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
16 Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]
17 Institute of Brain, Behaviour and Mental Health

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amy-loid 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 Keywords: Alzheimer APP ADAM30 Amyloid Metabolism LTP EBioMedicine 9 (2016) 278-292 Abbreviations: ADAM, A Disintegrin and Metalloproteinase Domain; APP, amyloid precursor protein; BACE, Beta-site APP cleaving enzyme 1; BSA, bovine serum albumin; CamKIIα, Ca2+/calmodulin-dependent protein kinase II alpha; COFRADIC, combined fractional diagonal chromatography; CTSD, cathepsin D; GKAP1, G kinase-anchoring protein 1; IRS4, insulin receptor substrate 4; LTP, long term potentiation; MMP, metalloproteinase; MRI, magnetic resonance imaging; PLA, proximity ligation assay; TD2, Type 2 diabetes. ⁎

Domaines: Neurosciences [q-bio.NC]

Florent Letronne, Geoffroy Laumet, Anne-Marie Ayral, Julien Chapuis, Florie Demiautte, et al.. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease. EBioMedicine, 2016, 9, pp.278-292. ⟨10.1016/j.ebiom.2016.06.002⟩. ⟨hal-02155738⟩