Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism.

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Vingtdeux, Valérie | Hamdane, Malika | Gompel, Marie | Begard, Severine | Drobecq, Hervé | Ghestem, Antoine | Eve Grosjean, Marie | Kostanjevecki, Vesna | Grognet, Pierre | Vanmechelen, Eugeen | Buee, Luc | Delacourte, André | Sergeant, Nicolas

Edité par CCSD ; Elsevier -

In Alzheimer's disease, the complex catabolism of amyloid precursor protein (APP) leads to the production of amyloid-beta (Abeta) peptide, the major component of amyloid deposits. APP is cleaved by beta- and alpha-secretases to generate APP carboxy-terminal fragments (CTFs). Abeta peptide and amyloid intracellular domain are resulting from the cleavage of APP-CTFs by the gamma-secretase. In the present study, we hypothesize that post-translational modification of APP-CTFs could modulate their processing by the gamma-secretase. Inhibition of the gamma-secretase was shown to increase the total amount of APP-CTFs. Moreover, we showed that this increase was more marked among the phosphorylated variants and directly related to the activity of the gamma-secretase, as shown by kinetics analyses. Phosphorylated CTFs were shown to associate to presenilin 1, a major protein of the gamma-secretase complex. The phosphorylation of CTFs at the threonine 668 resulting of the c-Jun N-terminal kinase activation was shown to enhance their degradation by the gamma-secretase. Altogether, our results demonstrated that phosphorylated CTFs can be the substrates of the gamma-secretase and that an increase in the phosphorylation of APP-CTFs facilitates their processing by gamma-secretase.

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