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

Valérie Vingtdeux (1) , Malika Hamdane (1) , Marie Gompel (1) , Severine Begard (1) , Hervé Drobecq (2) , Antoine Ghestem (1) , Marie Eve Grosjean (1) , Vesna Kostanjevecki , Pierre Grognet , Eugeen Vanmechelen , Luc Buee (1) , André Delacourte (1) , Nicolas Sergeant (1)

1 Neuroendocrinologie et physiopathologie neuronale
2 SSFB - Synthèse, structure et fonction des biomolécules

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.

Domaines: Biochimie, Biologie Moléculaire

Valérie Vingtdeux, Malika Hamdane, Marie Gompel, Severine Begard, Hervé Drobecq, et al.. Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism.. Neurobiology of Disease, 2005, 20, pp.625-37. ⟨hal-00098664⟩