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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
20
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pubmed:dateCreated |
2003-10-1
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pubmed:abstractText |
beta-Secretase (BACE, Asp-2) is a transmembrane aspartic proteinase responsible for cleaving the amyloid precursor protein (APP) to generate the soluble ectodomain sAPPbeta and its C-terminal fragment CTFbeta. CTFbeta is subsequently cleaved by gamma-secretase to produce the neurotoxic/synaptotoxic amyloid-beta peptide (Abeta) that accumulates in Alzheimer's disease. Indirect evidence has suggested that amyloidogenic APP processing may preferentially occur in lipid rafts. Here, we show that relatively little wild-type BACE is found in rafts prepared from a human neuroblastoma cell line (SH-SY5Y) by using Triton X-100 as detergent. To investigate further the significance of lipid rafts in APP processing, a glycosylphosphatidylinositol (GPI) anchor has been added to BACE, replacing the transmembrane and C-terminal domains. The GPI anchor targets the enzyme exclusively to lipid raft domains. Expression of GPIBACE substantially up-regulates the secretion of both sAPPbeta and amyloid-beta peptide over levels observed from cells overexpressing wild-type BACE. This effect was reversed when the lipid rafts were disrupted by depleting cellular cholesterol levels. These results suggest that processing of APP to the amyloid-beta peptide occurs predominantly in lipid rafts and that BACE is the rate-limiting enzyme in this process. The processing of the APP695 isoform by GPI-BACE was up-regulated 20-fold compared with wild-type BACE, whereas only a 2-fold increase in the processing of APP751/770 was seen, implying a differential compartmentation of the APP isoforms. Changes in the local membrane environment during aging may facilitate the cosegregation of APP and BACE leading to increased beta-amyloid production.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-10098859,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-10417979,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-10531052,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-10548529,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-10591214,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-10656250,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-10748135,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11030795,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11083922,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11089820,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11152688,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11224535,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11224536,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11296263,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11309494,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11344276,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11413487,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11485569,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-11525745,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-12052175,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-12392774,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-12515826,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-12691659,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-1531449,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-2881207,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-2893289,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-2893290,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-2893291,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-8346443,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-8631800,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-8940079,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-9153235,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-9600988,
http://linkedlifedata.com/resource/pubmed/commentcorrection/14504402-9837771
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0027-8424
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
30
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pubmed:volume |
100
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
11735-40
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:14504402-Amino Acid Sequence,
pubmed-meshheading:14504402-Amyloid Precursor Protein Secretases,
pubmed-meshheading:14504402-Amyloid beta-Protein Precursor,
pubmed-meshheading:14504402-Aspartic Acid Endopeptidases,
pubmed-meshheading:14504402-Cholesterol,
pubmed-meshheading:14504402-Endopeptidases,
pubmed-meshheading:14504402-Glycosylphosphatidylinositols,
pubmed-meshheading:14504402-Humans,
pubmed-meshheading:14504402-Hydrolysis,
pubmed-meshheading:14504402-Lipid Metabolism,
pubmed-meshheading:14504402-Molecular Sequence Data,
pubmed-meshheading:14504402-Protein Processing, Post-Translational,
pubmed-meshheading:14504402-Tumor Cells, Cultured
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pubmed:year |
2003
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pubmed:articleTitle |
Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein.
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pubmed:affiliation |
Proteolysis Research Group, School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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