Phosphorylation of amyloid precursor carboxy-terminal fragments enhances their processing by a gamma-secretase-dependent mechanism - PubMed (original) (raw)

doi: 10.1016/j.nbd.2005.05.004. Epub 2005 Jun 3.

Malika Hamdane, Marie Gompel, Séverine Bégard, Hervé Drobecq, Antoine Ghestem, Marie-Eve Grosjean, Vesna Kostanjevecki, Pierre Grognet, Eugeen Vanmechelen, Luc Buée, André Delacourte, Nicolas Sergeant

Affiliations

• PMID: 15936948
• DOI: 10.1016/j.nbd.2005.05.004

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

Valérie Vingtdeux et al. Neurobiol Dis. 2005 Nov.

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.

PubMed Disclaimer

Similar articles

• Proteolytic processing of the Alzheimer's disease amyloid precursor protein in brain and platelets.
  Evin G, Zhu A, Holsinger RM, Masters CL, Li QX. Evin G, et al. J Neurosci Res. 2003 Nov 1;74(3):386-92. doi: 10.1002/jnr.10745. J Neurosci Res. 2003. PMID: 14598315
• gamma-Secretase can cleave amyloid precursor protein fragments independent of alpha- and beta-secretase pre-cutting.
  Kume H, Sekijima Y, Maruyama K, Kametani F. Kume H, et al. Int J Mol Med. 2003 Jul;12(1):57-60. Int J Mol Med. 2003. PMID: 12792809
• Presenilin 1 regulates the processing of beta-amyloid precursor protein C-terminal fragments and the generation of amyloid beta-protein in endoplasmic reticulum and Golgi.
  Xia W, Zhang J, Ostaszewski BL, Kimberly WT, Seubert P, Koo EH, Shen J, Selkoe DJ. Xia W, et al. Biochemistry. 1998 Nov 24;37(47):16465-71. doi: 10.1021/bi9816195. Biochemistry. 1998. PMID: 9843412
• The Alzheimer's disease-associated gamma-secretase complex: functional domains in the presenilin 1 protein.
  Laudon H, Winblad B, Näslund J. Laudon H, et al. Physiol Behav. 2007 Sep 10;92(1-2):115-20. doi: 10.1016/j.physbeh.2007.05.037. Epub 2007 May 21. Physiol Behav. 2007. PMID: 17588625 Review.
• Presenilin, Notch, and the genesis and treatment of Alzheimer's disease.
  Selkoe DJ. Selkoe DJ. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11039-41. doi: 10.1073/pnas.211352598. Proc Natl Acad Sci U S A. 2001. PMID: 11572965 Free PMC article. Review.

Cited by

• Increased T-cell reactivity and elevated levels of CD8+ memory T-cells in Alzheimer's disease-patients and T-cell hyporeactivity in an Alzheimer's disease-mouse model: implications for immunotherapy.
  Schindowski K, Eckert A, Peters J, Gorriz C, Schramm U, Weinandi T, Maurer K, Frölich L, Müller WE. Schindowski K, et al. Neuromolecular Med. 2007;9(4):340-54. doi: 10.1007/s12017-007-8015-9. Epub 2007 Oct 26. Neuromolecular Med. 2007. PMID: 17963048
• Dyrk1a from Gene Function in Development and Physiology to Dosage Correction across Life Span in Down Syndrome.
  Atas-Ozcan H, Brault V, Duchon A, Herault Y. Atas-Ozcan H, et al. Genes (Basel). 2021 Nov 20;12(11):1833. doi: 10.3390/genes12111833. Genes (Basel). 2021. PMID: 34828439 Free PMC article. Review.
• Transthyretin Suppresses Amyloid-β Secretion by Interfering with Processing of the Amyloid-β Protein Precursor.
  Li X, Song Y, Sanders CR, Buxbaum JN. Li X, et al. J Alzheimers Dis. 2016 Apr 8;52(4):1263-75. doi: 10.3233/JAD-160033. J Alzheimers Dis. 2016. PMID: 27079720 Free PMC article.
• CD46 plasticity and its inflammatory bias in multiple sclerosis.
  Ni Choileain S, Astier AL. Ni Choileain S, et al. Arch Immunol Ther Exp (Warsz). 2011 Feb;59(1):49-59. doi: 10.1007/s00005-010-0109-7. Epub 2011 Jan 26. Arch Immunol Ther Exp (Warsz). 2011. PMID: 21267793 Free PMC article. Review.
• Tumor necrosis factor-alpha-elicited stimulation of gamma-secretase is mediated by c-Jun N-terminal kinase-dependent phosphorylation of presenilin and nicastrin.
  Kuo LH, Hu MK, Hsu WM, Tung YT, Wang BJ, Tsai WW, Yen CT, Liao YF. Kuo LH, et al. Mol Biol Cell. 2008 Oct;19(10):4201-12. doi: 10.1091/mbc.e07-09-0987. Epub 2008 Jul 30. Mol Biol Cell. 2008. PMID: 18667537 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Medical

  • MedlinePlus Health Information

• Research Materials

  • NCI CPTC Antibody Characterization Program

• Miscellaneous

  • NCI CPTAC Assay Portal