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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2005-4-26
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pubmed:abstractText |
Abnormal production and accumulation of amyloid-beta peptide (Abeta) plays a major role in the pathogenesis of Alzheimer's disease (AD). beta-secretase (BACE1) is responsible for the cleavage at thebeta-site in amyloid beta protein precursor (AbetaPP/APP) to generate the N-terminus of Abeta. Here we report the stepwise identification and characterization of a novel APP-beta-site mutant, "NFEV" (APP_NFEV) in vitro and in cells. In vitro, the APP_NFEV exhibits 100-fold enhanced cleavage rate relative to the "wild-type" substrate (APPwt) and 10-fold increase relative to the Swedish-type mutation variant (APPsw). In cells, it was preferably cleaved among 24 APP beta-site mutations tested. More importantly, the APP_NFEV mutant failed to generate any detectable Abeta peptides in BACE1-KO mouse fibroblast cells. The production of Abeta peptides was restored by co-transfecting human BACE1, demonstrating that BACE1 is the only enzyme responsible for the processing of APP_NFEV in these cells. Analysis of APP_NFEV cleavage products secreted in the media revealed that in cells BACE1 cleaves APP_NFEV at the position between NF and EV, identical to that observed in vitro. A BACE inhibitor blocked the processing of the APP_NFEV beta-site in vitro and in cells. Our data indicates that the "NFEV" mutant is not only an enhanced substrate for BACE1 in vitro, but also a specific substrate for BACE1 in cells.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid Precursor Protein Secretases,
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Protein Precursor,
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/BACE1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/BACE2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Bace1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/amyloid beta-peptide (5-40)
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1387-2877
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pubmed:author |
pubmed-author:BruceJames EJE,
pubmed-author:Chen-DodsonElizabethE,
pubmed-author:ComiG PGP,
pubmed-author:CrouthamelMing-ChihMC,
pubmed-author:DiMuzioJillianJ,
pubmed-author:EspesethAmyA,
pubmed-author:GarskyVictorV,
pubmed-author:HazudaDaria JDJ,
pubmed-author:HuBinghuaB,
pubmed-author:HuangQianQ,
pubmed-author:KahanaJasonJ,
pubmed-author:LANVV,
pubmed-author:LaiMing-TainMT,
pubmed-author:LiYuemingY,
pubmed-author:LinebergerJanetJ,
pubmed-author:LuckaAdamA,
pubmed-author:MillerRonR,
pubmed-author:PietrakBethB,
pubmed-author:PriceEricE,
pubmed-author:RegisterRobert BRB,
pubmed-author:SankaranarayananSethuS,
pubmed-author:SardanaMohinder KMK,
pubmed-author:ShiXiao-PingXP,
pubmed-author:SimonAdamA,
pubmed-author:TangMei-JyMJ,
pubmed-author:TugushevaKatherineK,
pubmed-author:WolfeAbigailA,
pubmed-author:WuGuo-XinGX
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pubmed:issnType |
Print
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pubmed:volume |
7
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
139-48; discussion 173-80
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:15851852-Alzheimer Disease,
pubmed-meshheading:15851852-Amyloid Precursor Protein Secretases,
pubmed-meshheading:15851852-Amyloid beta-Peptides,
pubmed-meshheading:15851852-Amyloid beta-Protein Precursor,
pubmed-meshheading:15851852-Animals,
pubmed-meshheading:15851852-Antibodies, Monoclonal,
pubmed-meshheading:15851852-Aspartic Acid Endopeptidases,
pubmed-meshheading:15851852-Disease Models, Animal,
pubmed-meshheading:15851852-Endopeptidases,
pubmed-meshheading:15851852-Enzyme Activation,
pubmed-meshheading:15851852-Fibroblasts,
pubmed-meshheading:15851852-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:15851852-Mice,
pubmed-meshheading:15851852-Molecular Sequence Data,
pubmed-meshheading:15851852-Peptide Fragments,
pubmed-meshheading:15851852-Point Mutation,
pubmed-meshheading:15851852-Substrate Specificity,
pubmed-meshheading:15851852-Transfection
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pubmed:year |
2005
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pubmed:articleTitle |
Novel mutations introduced at the beta-site of amyloid beta protein precursor enhance the production of amyloid beta peptide by BACE1 in vitro and in cells.
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pubmed:affiliation |
Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. xiao-ping_shi@merck.com
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pubmed:publicationType |
Journal Article,
In Vitro
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