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Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gamma-secretase activity.
J Biol Chem. 2004 Jun 11; 279(24):25333-8.JB

Abstract

The cleavage of the transmembrane amyloid precursor protein (APP) by beta-secretase leaves the C-terminal fragment of APP, C99, anchored in the plasma membrane. C99 is subsequently processed by gamma-secretase, an unusual aspartyl protease activity largely dependent on presenilin (PS), generating the amyloid beta-peptide (Abeta) that accumulates in the brain of patients with Alzheimer's disease. It has been suggested that PS proteins are the catalytic core of this proteolytic activity, but a number of other proteins mandatory for gamma-secretase cleavage have also been discovered. The exact role of PS in the gamma-secretase activity remains a matter of debate, because cells devoid of PS still produce some forms of Abeta. Here, we used insect cells expressing C99 to demonstrate that the expression of presenilin 1 (PS1), which binds C99, not only increases the production of Abeta by these cells but also increases the intracellular levels of C99 to the same extent. Using pulse-chase experiments, we established that this results from an increased half-life of C99 in cells expressing PS1. In Chinese hamster ovary cells producing C99 from full-length human APP, similar results were observed. Finally, we show that a functional inhibitor of gamma-secretase does not alter the ability of PS1 to increase the intracellular levels of C99. This finding suggests that the binding of PS1 to C99 does not necessarily lead to its immediate cleavage by gamma-secretase, which could be a spatio-temporally regulated or an induced event, and provides biochemical evidence for the existence of a substrate-docking site on PS1.

Authors+Show Affiliations

Laboratoire de Pharmacologie Expérimentale, Université Catholique de Louvain, 1200 Brussels, Belgium.No affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15087467

Citation

Pitsi, Didier, and Jean-Noël Octave. "Presenilin 1 Stabilizes the C-terminal Fragment of the Amyloid Precursor Protein Independently of Gamma-secretase Activity." The Journal of Biological Chemistry, vol. 279, no. 24, 2004, pp. 25333-8.
Pitsi D, Octave JN. Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gamma-secretase activity. J Biol Chem. 2004;279(24):25333-8.
Pitsi, D., & Octave, J. N. (2004). Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gamma-secretase activity. The Journal of Biological Chemistry, 279(24), 25333-8.
Pitsi D, Octave JN. Presenilin 1 Stabilizes the C-terminal Fragment of the Amyloid Precursor Protein Independently of Gamma-secretase Activity. J Biol Chem. 2004 Jun 11;279(24):25333-8. PubMed PMID: 15087467.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presenilin 1 stabilizes the C-terminal fragment of the amyloid precursor protein independently of gamma-secretase activity. AU - Pitsi,Didier, AU - Octave,Jean-Noël, Y1 - 2004/04/15/ PY - 2004/4/17/pubmed PY - 2004/7/2/medline PY - 2004/4/17/entrez SP - 25333 EP - 8 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 279 IS - 24 N2 - The cleavage of the transmembrane amyloid precursor protein (APP) by beta-secretase leaves the C-terminal fragment of APP, C99, anchored in the plasma membrane. C99 is subsequently processed by gamma-secretase, an unusual aspartyl protease activity largely dependent on presenilin (PS), generating the amyloid beta-peptide (Abeta) that accumulates in the brain of patients with Alzheimer's disease. It has been suggested that PS proteins are the catalytic core of this proteolytic activity, but a number of other proteins mandatory for gamma-secretase cleavage have also been discovered. The exact role of PS in the gamma-secretase activity remains a matter of debate, because cells devoid of PS still produce some forms of Abeta. Here, we used insect cells expressing C99 to demonstrate that the expression of presenilin 1 (PS1), which binds C99, not only increases the production of Abeta by these cells but also increases the intracellular levels of C99 to the same extent. Using pulse-chase experiments, we established that this results from an increased half-life of C99 in cells expressing PS1. In Chinese hamster ovary cells producing C99 from full-length human APP, similar results were observed. Finally, we show that a functional inhibitor of gamma-secretase does not alter the ability of PS1 to increase the intracellular levels of C99. This finding suggests that the binding of PS1 to C99 does not necessarily lead to its immediate cleavage by gamma-secretase, which could be a spatio-temporally regulated or an induced event, and provides biochemical evidence for the existence of a substrate-docking site on PS1. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15087467/Presenilin_1_stabilizes_the_C_terminal_fragment_of_the_amyloid_precursor_protein_independently_of_gamma_secretase_activity_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15087467 DB - PRIME DP - Unbound Medicine ER -