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 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 A peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30 mut) did not affect A 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 A42 secretion in neuron primary cultures, soluble A42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation.
Cite
@article{arxiv.1906.07511,
title = {ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease},
author = {Florent Letronne and Geoffroy Laumet and Anne-Marie Ayral and Julien Chapuis and Florie Demiautte and Mathias Laga and Michel Vandenberghe and Nicolas Malmanche and Florence Leroux and Fanny Eysert and Yoann Sottejeau and Linda Chami and Amandine Flaig and Charlotte Bauer and Pierre Dourlen and Marie Lesaffre and Charlotte Delay and Ludovic Huot and Julie Dumont and Elisabeth Werkmeister and Franck Lafont and Tiago Mendes and Franck Hansmannel and Bart Dermaut and Benoit Deprez and Anne-Sophie Herard and Marc Dhenain and Nicolas Souedet and Florence Pasquier and David Tulasne and Claudine Berr and Jean-Jacques Hauw and Yves Lemoine and Philippe Amouyel and David Mann and Rebecca Déprez and Frédéric Checler and David Hot and Thierry Delzescaux and Kris Gevaert and Jean-Charles Lambert},
journal= {arXiv preprint arXiv:1906.07511},
year = {2019}
}