7^e Colloque de la Société des neurosciences

May 18-20, 2005, Lille (France)

For lectures and symposia, time indicates the beginning of the session.
For posters, authors are expected to be present at the time indicated.

Poster I-44 - 20/05/05, 14:00 - Lille Métropole I
Session I - Molecular and Cellular Neurobiology III
Ref.: 7^e Colloque de la Société des neurosciences, Lille 2005, I.44.

Author(s)	Vingtdeux V. (1), Hamdane M. (1), Gompel M. (1), Bégard S. (1), Ghestem A. (1), Vanmechelen E. (2), Delacourte A. (1), Buée L. (1) & Sergeant N. (1)
Addresse(s)	(1) Inserm U422, Lille, France ; (2) Innogenetics NV, Zwinjnaarde, Belgium
Title	Phosphorylation of amyloid precursor protein carboxy-terminal fragments facilitates their processing by gamma-secretase.
Text	Amyloid-beta (Abeta), the major component of amyloid deposits in Alzheimer disease, derives from a complex catabolism of amyloid precursor protein (APP). Gamma-secretase proteolytic activity generates Abeta peptides and the APP intracellular domain (AICD) from the carboxy-terminal fragments (CTF) of the APP. Potential intrinsic modulators of this event are not known. To address this issue, SH-SY5Y cells stably expressing the human APP were treated with gamma-secretase inhibitors and APP-CTFs were analysed by a proteomic approach. Following gamma-secretase inhibition, beta- and alpha-secretase derived APP-CTFs were increased, whereas both Abeta1-42 and AICD were reduced. Interestingly, phosphorylated variants of APP-CTFs including the Thr668 site were strongly increased following the treatment, suggesting that phosphorylation could modulate the processing of beta- and alpha-CTFs. In this way we showed that phosphorylated APP-CTFs at Thr668 are more rapidly processed by gamma-secretase than non-phosphorylated variants. These Thr668 phosphorylated APP-CTFs co-immunoprecipitated with PS1 (which is the major component of the gamma-secretase complex) only when gamma-secretase activity is abolished. Furthermore, induced phosphorylation of those CTFs following the activation of c-Jun N-terminal kinase enhanced the degradation of beta- and alpha-CTFs which was completely abolished by gamma-secretase inhibitor. Together, our data demonstrate that phosphorylation facilitates APP-CTFs processing by gamma-secretase. Modulation of the phosphorylation of beta- and alpha-CTFs is therefore an interesting therapeutic target in Alzheimer's disease.