Dataset Information

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 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 A?42 secretion in neuron primary cultures, soluble A?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? production, thereby contributing to Alzheimer's disease development.

SUBMITTER: Letronne F

PROVIDER: S-EPMC4972530 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Letronne Florent F Laumet Geoffroy G Ayral Anne-Marie AM Chapuis Julien J Demiautte Florie F Laga Mathias M Vandenberghe Michel E ME Malmanche Nicolas N Leroux Florence F Eysert Fanny F Sottejeau Yoann Y Chami Linda L Flaig Amandine A Bauer Charlotte C Dourlen Pierre P Lesaffre Marie M Delay Charlotte C Huot Ludovic L Dumont Julie J Werkmeister Elisabeth E Lafont Franck F Mendes Tiago T Hansmannel Franck F Dermaut Bart B Deprez Benoit B Hérard Anne-Sophie AS Dhenain Marc M Souedet Nicolas N Pasquier Florence F Tulasne David D Berr Claudine C Hauw Jean-Jacques JJ Lemoine Yves Y Amouyel Philippe P Mann David D Déprez Rebecca R Checler Frédéric F Hot David D Delzescaux Thierry T Gevaert Kris K Lambert Jean-Charles JC

EBioMedicine 20160602

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 incr ...[more]

PMID: 27333034

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Project description:Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing.The human APP, ?CTF and A?42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks.Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, ?CTF and A?42/A?40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.

Dataset Information

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

Publications

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

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