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Phosphorylation of APP695 at Thr668 decreases gamma-cleavage and extracellular Abeta.

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Feyt, Christine [UCL] Courtoy, Pierre J. [UCL] Pierrot, Nathalie [UCL] Tasiaux, Bernadette [UCL] Van Hees, Joanne [UCL] Kienlen-Campard, Pascal [UCL] Octave, Jean-Noël [UCL]

Phosphorylation of human APP695 at Thr668 seems to be specific to neuronal tissue and could affect Abeta production. Metabolism of APP mutated at Thr668 residue was analyzed in CHO cell line and primary cultures of rat cortical neurons. By site-directed mutagenesis, T668A or T668D substitutions were introduced in wild-type APP695. In CHO cells, wild-type APP695 was very slightly phosphorylated at Thr668 and produced similar levels of extracellular Abeta40 as compared to APPT668A. On the contrary, APPT668D was more efficiently cleaved by beta-secretase. However, accumulated betaCTF were less cleaved by gamma-secretase and less extracellular Abeta40 was produced. Decreased susceptibility to cleavage by gamma-secretase was confirmed upon expression of C99T668D. In neurons, part of APP695 was phosphorylated at Thr668. Following neuronal expression of APPT668A, extracellular Abeta40 production was increased. In conclusion, phosphorylation of human APP695 at Thr668 increases APP beta-cleavage but decreases its gamma-cleavage and extracellular Abeta40 production.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2007
Journal information "Biochemical and biophysical research communications" - Vol. 357, no. 4, p. 1004-10 (2007)
Peer reviewed yes
issn 0006-291X
Publication status Publié
Affiliations UCL - MD/FSIO - Département de physiologie et pharmacologie
UCL - MD/BICL - Département de biochimie et de biologie cellulaire
UCL - MD/MIGE - Département de microbiologie, d'immunologie et de génétique
MESH Subject Amyloid beta-Protein ; Amyloid beta-Protein Precursor - metabolism ; Animals ; Binding Sites ; CHO Cells ; Cells, Cultured ; Cricetinae ; Cricetulus ; Extracellular Fluid - metabolism ; Mutagenesis, Site-Directed ; Neurons - metabolism ; Peptide Fragments - metabolism ; Phosphorylation ; Protein Binding ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; Threonine - metabolism
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Bibliographic reference Feyt, Christine ; Courtoy, Pierre J. ; Pierrot, Nathalie ; Tasiaux, Bernadette ; Van Hees, Joanne ; et. al. Phosphorylation of APP695 at Thr668 decreases gamma-cleavage and extracellular Abeta.. In: Biochemical and biophysical research communications, Vol. 357, no. 4, p. 1004-10 (2007)
Permanent URL http://hdl.handle.net/2078.1/10942