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ADAM30 downregulates APP-linked defects through cathepsin D activation in Alzheimer's disease

(2016) EBIOMEDICINE. 9. p.278-292
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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 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 alterations. Our data thus indicate that lowering ADAM30 expression may favor A beta production, thereby contributing to Alzheimer's disease development. (C) 2016 The Authors. Published by Elsevier B.V.
Keywords
MICE, ROLES, BRAIN, DEGRADATION, GENE-EXPRESSION, COGNITIVE DECLINE, ALPHA-SECRETASE, TRANSGENIC MOUSE MODEL, AMYLOID PRECURSOR PROTEIN, Metabolism, LTP, Amyloid, ADAM30, APP, Alzheimer, INHIBITORS

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Chicago
Letronne, Florent, Geoffroy Laumet, Anne-Marie Ayral, Julien Chapuis, Florie Demiautte, Mathias Laga, Michel E Vandenberghe, et al. 2016. “ADAM30 Downregulates APP-linked Defects Through Cathepsin D Activation in Alzheimer’s Disease.” Ebiomedicine 9: 278–292.
APA
Letronne, F., Laumet, G., Ayral, A.-M., Chapuis, J., Demiautte, F., Laga, M., Vandenberghe, M. E., et al. (2016). ADAM30 downregulates APP-linked defects through cathepsin D activation in Alzheimer’s disease. EBIOMEDICINE, 9, 278–292.
Vancouver
1.
Letronne F, Laumet G, Ayral A-M, Chapuis J, Demiautte F, Laga M, et al. ADAM30 downregulates APP-linked defects through cathepsin D activation in Alzheimer’s disease. EBIOMEDICINE. 2016;9:278–92.
MLA
Letronne, Florent, Geoffroy Laumet, Anne-Marie Ayral, et al. “ADAM30 Downregulates APP-linked Defects Through Cathepsin D Activation in Alzheimer’s Disease.” EBIOMEDICINE 9 (2016): 278–292. Print.
@article{8201477,
  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 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 alterations. Our data thus indicate that lowering ADAM30 expression may favor A beta production, thereby contributing to Alzheimer's disease development. (C) 2016 The Authors. Published by Elsevier B.V.},
  author       = {Letronne, Florent and Laumet, Geoffroy and Ayral, Anne-Marie and Chapuis, Julien and Demiautte, Florie and Laga, Mathias and Vandenberghe, Michel E and Malmanche, Nicolas and Leroux, Florence and Eysert, Fanny and Sottejeau, Yoann and Chami, Linda and Flaig, Amandine and Bauer, Charlotte and Dourlen, Pierre and Lesaffre, Marie and Delay, Charlotte and Huot, Ludovic and Dumont, Julie and Werkmeister, Elisabeth and Lafont, Franck and Mendes, Tiago and Hansmannel, Franck and Dermaut, Bart and Deprez, Benoit and H{\'e}rard, Anne-Sophie and Dhenain, Marc and Souedet, Nicolas and Pasquier, Florence and Tulasne, David and Berr, Claudine and Hauw, Jean-Jacques and Lemoine, Yves and Amouyel, Philippe and Mann, David and D{\'e}prez, Rebecca and Checler, Fr{\'e}d{\'e}ric and Hot, David and Delzescaux, Thierry and Gevaert, Kris and Lambert, Jean-Charles},
  issn         = {2352-3964},
  journal      = {EBIOMEDICINE},
  keyword      = {MICE,ROLES,BRAIN,DEGRADATION,GENE-EXPRESSION,COGNITIVE DECLINE,ALPHA-SECRETASE,TRANSGENIC MOUSE MODEL,AMYLOID PRECURSOR PROTEIN,Metabolism,LTP,Amyloid,ADAM30,APP,Alzheimer,INHIBITORS},
  language     = {eng},
  pages        = {278--292},
  title        = {ADAM30 downregulates APP-linked defects through cathepsin D activation in Alzheimer's disease},
  url          = {http://dx.doi.org/10.1016/j.ebiom.2016.06.002},
  volume       = {9},
  year         = {2016},
}

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