Home LiteratureArticle Details
PMID: 20675367 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Dual role of alpha-secretase cleavage in the regulation of gamma-secretase activity for amyloid production.

The Journal of biological chemistry ·Vol. 285 ·No. 42 ·2010-10-15 ·Pages 32549-56

Tian Y, Crump CJ, Li YM

Abstract

Processing of the amyloid precursor protein (APP) by β- and γ-secretases generates pathogenic β-amyloid (Aβ) peptides associated with Alzheimer disease (AD), whereas cleavage of APP by α-secretases precludes Aβ formation. Little is known about the role of α-secretase cleavage in γ-secretase regulation. Here, we show that α-secretase-cleaved APP C-terminal product (αCTF) functions as an inhibitor of γ-secretase. We demonstrate that the substrate inhibitory domain (ASID) within αCTF, which is bisected by the α-secretase cleavage site, contributes to this negative regulation because deleting or masking this domain turns αCTF into a better substrate for γ-secretase. Moreover, α-secretase cleavage can potentiate the inhibitory effect of ASID. Inhibition of γ-secretase activity by αCTF is observed in both in vitro and cellular systems. This work reveals an unforeseen role for α-secretase in generating an endogenous γ-secretase inhibitor that down-regulates the production of Aβ. Deregulation of this feedback mechanism may contribute to the pathogenesis of AD.

MeSH Terms
ADAM Proteins/genetics,metabolism ADAM10 Protein ADAM17 Protein Alzheimer Disease/metabolism Amino Acid Sequence Amyloid/genetics,metabolism Amyloid Precursor Protein Secretases/antagonists & inhibitors,genetics,metabolism Amyloid beta-Protein Precursor/genetics,metabolism Animals Cell Line Humans Membrane Proteins/genetics,metabolism Molecular Sequence Data Peptides/genetics,metabolism
Chemicals
Amyloid Amyloid beta-Protein Precursor Membrane Proteins Peptides Amyloid Precursor Protein Secretases ADAM Proteins ADAM10 Protein ADAM10 protein, human ADAM17 Protein
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Tian Yuan
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Crump Christina J
Li Yue-Ming
References (33)
33 references, click to expand
  1. Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases.
    Cell. 2001 Oct 19;107(2):173-82 PMID: 11672525
  2. Presenilin 1 is linked with gamma-secretase activity in the detergent solubilized state.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):6138-43 PMID: 10801983
  3. Alpha-secretase as a therapeutic target.
    Curr Alzheimer Res. 2007 Sep;4(4):412-7 PMID: 17908044
  4. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease.
    Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3922-7 PMID: 10097139
  5. Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling.
    Cell. 2006 Jul 14;126(1):163-75 PMID: 16839884
  6. Mutational analysis of potential zinc-binding residues in the active site of the enterococcal D-Ala-D-Ala dipeptidase VanX.
    Biochemistry. 1997 Aug 26;36(34):10498-505 PMID: 9265630
  7. Glu-333 of nicastrin directly participates in gamma-secretase activity.
    J Biol Chem. 2009 Oct 23;284(43):29714-24 PMID: 19729449
  8. Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer's disease.
    Nat Med. 1995 Aug;1(8):829-32 PMID: 7585189
  9. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity.
    Biochemistry. 2000 Aug 1;39(30):8698-704 PMID: 10913280
  10. {gamma}-Secretase Substrate Concentration Modulates the Abeta42/Abeta40 Ratio: IMPLICATIONS FOR ALZHEIMER DISEASE.
    J Biol Chem. 2007 Aug 10;282(32):23639-44 PMID: 17556361
  11. Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients.
    Exp Neurol. 2003 Sep;183(1):74-80 PMID: 12957490
  12. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease.
    Nature. 2003 May 29;423(6939):537-41 PMID: 12774122
  13. Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid-beta precursor protein in the trans-golgi network.
    J Biol Chem. 2000 Jan 28;275(4):2568-75 PMID: 10644715
  14. Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin.
    J Neurosci. 2010 Feb 3;30(5):1648-56 PMID: 20130175
  15. Glu(332) in the Nicastrin ectodomain is essential for gamma-secretase complex maturation but not for its activity.
    J Biol Chem. 2008 Jul 18;283(29):20096-105 PMID: 18502756
  16. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism.
    Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):403-9 PMID: 17197420
  17. Characterization of an atypical gamma-secretase complex from hematopoietic origin.
    Biochemistry. 2010 Apr 6;49(13):2796-804 PMID: 20178366
  18. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.
    Cell. 2000 Feb 18;100(4):391-8 PMID: 10693756
  19. A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model.
    J Clin Invest. 2004 May;113(10):1456-64 PMID: 15146243
  20. Modulation of gamma-secretase specificity using small molecule allosteric inhibitors.
    Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20228-33 PMID: 19906985
  21. An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for Abeta production.
    Nat Struct Mol Biol. 2010 Feb;17(2):151-8 PMID: 20062056
  22. Gender- and age-dependent gamma-secretase activity in mouse brain and its implication in sporadic Alzheimer disease.
    PLoS One. 2009;4(4):e5088 PMID: 19352431
  23. alpha- and beta-secretase: profound changes in Alzheimer's disease.
    Biochem Biophys Res Commun. 2002 Dec 6;299(3):373-6 PMID: 12445809
  24. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.
    Science. 1992 Oct 9;258(5080):304-7 PMID: 1411529
  25. The non-amyloidogenic pathway: structure and function of alpha-secretases.
    Subcell Biochem. 2005;38:105-27 PMID: 15709475
  26. A miniaturized 1536-well format gamma-secretase assay.
    Assay Drug Dev Technol. 2009 Oct;7(5):461-70 PMID: 19715456
  27. Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate.
    Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2720-5 PMID: 11867728
  28. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor.
    J Biol Chem. 1998 Oct 23;273(43):27765-7 PMID: 9774383
  29. Amyloid deposition as the central event in the aetiology of Alzheimer's disease.
    Trends Pharmacol Sci. 1991 Oct;12(10):383-8 PMID: 1763432
  30. Levels of alpha- and beta-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer's disease patients.
    Neurosci Lett. 2000 Jan 14;278(3):169-72 PMID: 10653020
  31. Nicastrin functions as a gamma-secretase-substrate receptor.
    Cell. 2005 Aug 12;122(3):435-47 PMID: 16096062
  32. Amyloid precursor protein trafficking, processing, and function.
    J Biol Chem. 2008 Oct 31;283(44):29615-9 PMID: 18650430
  33. An exo-cell assay for examining real-time gamma-secretase activity and inhibition.
    Mol Neurodegener. 2009 Jun 02;4:22 PMID: 19490610
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M110.128439
Published
2010-10-15
Epub
2010-00-30
Pages
32549-56
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2952257
Subset
IM
Grants
NIA NIH HHS · R01 AG026660 · United States
NIGMS NIH HHS · T32 GM073546 · United States
NIA NIH HHS · AG026660 · United States
External Links
PubMed source DOI: 10.1074/jbc.M110.128439 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2