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Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism.
Neurobiol Dis. 2005 Nov; 20(2):625-37.ND

Abstract

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.

Authors+Show Affiliations

Department of Cerebral Aging and Neurodegeneration, INSERM U422, 1, place de Verdun, 59045 Lille, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15936948

Citation

Vingtdeux, Valérie, et al. "Phosphorylation of Amyloid Precursor Carboxy-terminal Fragments Enhances Their Processing By a Gamma-secretase-dependent Mechanism." Neurobiology of Disease, vol. 20, no. 2, 2005, pp. 625-37.
Vingtdeux V, Hamdane M, Gompel M, et al. Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism. Neurobiol Dis. 2005;20(2):625-37.
Vingtdeux, V., Hamdane, M., Gompel, M., Bégard, S., Drobecq, H., Ghestem, A., Grosjean, M. E., Kostanjevecki, V., Grognet, P., Vanmechelen, E., Buée, L., Delacourte, A., & Sergeant, N. (2005). Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism. Neurobiology of Disease, 20(2), 625-37.
Vingtdeux V, et al. Phosphorylation of Amyloid Precursor Carboxy-terminal Fragments Enhances Their Processing By a Gamma-secretase-dependent Mechanism. Neurobiol Dis. 2005;20(2):625-37. PubMed PMID: 15936948.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism. AU - Vingtdeux,Valérie, AU - Hamdane,Malika, AU - Gompel,Marie, AU - Bégard,Séverine, AU - Drobecq,Hervé, AU - Ghestem,Antoine, AU - Grosjean,Marie-Eve, AU - Kostanjevecki,Vesna, AU - Grognet,Pierre, AU - Vanmechelen,Eugeen, AU - Buée,Luc, AU - Delacourte,André, AU - Sergeant,Nicolas, Y1 - 2005/06/03/ PY - 2005/01/28/received PY - 2005/04/11/revised PY - 2005/05/02/accepted PY - 2005/6/7/pubmed PY - 2006/1/24/medline PY - 2005/6/7/entrez SP - 625 EP - 37 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 20 IS - 2 N2 - 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. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/15936948/Phosphorylation_of_amyloid_precursor_carboxy_terminal_fragments_enhances_their_processing_by_a_gamma_secretase_dependent_mechanism_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(05)00143-9 DB - PRIME DP - Unbound Medicine ER -