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: Florent Letronne, Geoffroy Laumet, Anne-Marie Ayral, Julien Chapuis, Florie Demiautte, Mathias Laga, Michel E Vandenberghe, Nicolas Malmanche, Florence Leroux, Fanny Eysert, Yoann Sottejeau, Linda Chami, Amandine Flaig, Charlotte Bauer, Pierre Dourlen, Marie Lesaffre, Charlotte Delay, Ludovic Huot, Julie Dumont, Elisabeth Werkmeister, Franck Lafont, Tiago Mendes, Franck Hansmannel, Bart Dermaut, Benoit Deprez, Anne-Sophie Hérard, Marc Dhenain, Nicolas Souedet, Florence Pasquier, David Tulasne, Claudine Berr, Jean-Jacques Hauw, Yves Lemoine, Philippe Amouyel, David Mann, Rebecca Déprez, Frédéric Checler, David Hot, Thierry Delzescaux, Kris Gevaert, Jean-Charles Lambert
• Journal: EBioMedicine (EBioMedicine) Vol. 9 Pg. 278-292 (Jul 2016) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 27333034 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Macrolides
• Pepstatins
• RNA, Small Interfering
• bafilomycin A
• Cathepsin D
• ADAM Proteins
• ADAM30 protein, human
• pepstatin

Topics

• ADAM Proteins (antagonists & inhibitors, genetics, metabolism)
• Alzheimer Disease (metabolism, pathology)
• Amino Acid Sequence
• Amyloid beta-Peptides (metabolism)
• Animals
• Brain (metabolism, pathology)
• Cathepsin D (chemistry, metabolism)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• HEK293 Cells
• Humans
• Lysosomes (metabolism)
• Macrolides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microscopy, Fluorescence
• Patch-Clamp Techniques
• Pepstatins (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)