P2‐242: Characterization of a new ADAM as a key player of the APP metabolism

The APP metabolism is believed to play a central role in the Alzheimer's disease (AD) physiopathological process. However, this metabolism is still not fully characterised and among the protein families potentially involved, the metalloprotease one appears to be of particular interest. To identify new actors of the APP metabolism, we performed transcriptomic analysis of 132 genes of this large metalloprotease family using brain tissue of AD cases and controls. From 4 differentially expressed genes, we selected an ADAM as a relevant candidate following (i) confirmation of its decreased expression in AD brains and (ii) observation of an inverse correlation between its expression and parenchymal Aßx-42 loads. We determined that this ADAM is specifically expressed in neurons and at a sub-cellular level is localized in Golgi apparatus and endoplasmic reticulum. In vitro experiments indicated that this ADAM over-expression was associated with a decrease in production of all the APP metabolism by products. Inversely, shRNA experiments showed that a decrease in this ADAM expression was consistently associated with an increase in this metabolism. The effect on the APP metabolism was dependent on the ADAM catalytic site and on lysosomal pathway as observed by drug treatment experiments. Consistently, the ADAM over-expression was also associated with an increase in Cathepsin D activity and the 8 last amino-acids of the APP C-ter tail, known to potentially control sorting of APP to lysosome, appeared necessary for the ADAM-dependent modulation of the APP metabolism In conclusion, we postulate that a new ADAM may be involved in a new metabolic pathway, controlling APP sorting and degradation before α-, ß- and γ-secretase processing and involving lysosome activation.