1. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease
- Author
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Letronne, Florent, Laumet, Geoffroy, Ayral, Anne-Marie, Chapuis, Julien, Demiautte, Florie, Laga, Mathias, Vandenberghe, Michel, Malmanche, Nicolas, Leroux, Florence, Eysert, Fanny, Sottejeau, Yoann, Chami, Linda, Flaig, Amandine, Bauer, Charlotte, Dourlen, Pierre, Lesaffre, Marie, Delay, Charlotte, Huot, Ludovic, Dumont, Julie, Werkmeister, Elisabeth, Lafont, Franck, Mendes, Tiago, Hansmannel, Franck, Dermaut, Bart, Deprez, Benoit, Herard, Anne-Sophie, Dhenain, Marc, Souedet, Nicolas, Pasquier, Florence, Tulasne, David, Berr, Claudine, Hauw, Jean-Jacques, Lemoine, Yves, Amouyel, Philippe, Mann, David, Déprez, Rebecca, Checler, Frédéric, Hot, David, Delzescaux, Thierry, Gevaert, Kris, and Lambert, Jean-Charles
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Quantitative Biology - Neurons and Cognition ,Quantitative Biology - Tissues and Organs - 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$\beta$ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30 mut) did not affect A$\beta$ 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 A$\beta$42 secretion in neuron primary cultures, soluble A$\beta$42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation.
- Published
- 2019
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