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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2000-2-23
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pubmed:abstractText |
The deposition of amyloid-beta peptides (Abeta) in senile plaques (SPs) is a central pathological feature of Alzheimer's disease (AD). Since SPs are composed predominantly of Abeta1-42, which is more amyloidogenic in vitro, the enzymes involved in generating Abeta1-42 may be particularly important to the pathogenesis of AD. In contrast to Abeta1-40, which is generated in the trans-Golgi network and other cytoplasmic organelles, intracellular Abeta1-42 is produced in the endoplasmic reticulum/intermediate compartment (ER/IC), where it accumulates in a stable insoluble pool. Since this pool of insoluble Abeta1-42 may play a critical role in AD amyloidogenesis, we sought to determine how the production of intracellular Abeta is regulated. Surprisingly, the production of insoluble intracellular Abeta1-42 was increased by a putative gamma-secretase inhibitor as well as by an inhibitor of the proteasome. We further demonstrate that this increased generation of Abeta1-42 in the ER/IC is due to a reduction in the turnover of Abeta-containing APP C-terminal fragments. We conclude that the proteasome is a novel site for degradation of ER/IC-generated APP fragments. Proteasome inhibitors may augment the availability of APP C-terminal fragments for gamma-secretase cleavage and thereby increase production of Abeta1-42 in the ER/IC. Based on the organelle-specific differences in the generation of Abeta by gamma-secretase, we conclude that intracellular ER/IC-generated Abeta1-42 and secreted Abeta1-40 are produced by different gamma-secretases. Further, the fact that a putative gamma-secretase inhibitor had opposite effects on the production of secreted and intracellular Abeta may have important implications for AD drug design.
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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/Acetylcysteine,
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/Aspartic Acid Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/BACE1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Proteinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Leupeptins,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Peptide Fragments,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/amyloid beta-protein (1-42),
http://linkedlifedata.com/resource/pubmed/chemical/benzyloxycarbonylleucyl-leucyl-leuci...,
http://linkedlifedata.com/resource/pubmed/chemical/lactacystin
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0006-2960
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
39
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
810-7
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:10651647-Acetylcysteine,
pubmed-meshheading:10651647-Amyloid Precursor Protein Secretases,
pubmed-meshheading:10651647-Amyloid beta-Peptides,
pubmed-meshheading:10651647-Amyloid beta-Protein Precursor,
pubmed-meshheading:10651647-Animals,
pubmed-meshheading:10651647-Aspartic Acid Endopeptidases,
pubmed-meshheading:10651647-Binding, Competitive,
pubmed-meshheading:10651647-CHO Cells,
pubmed-meshheading:10651647-Cell Compartmentation,
pubmed-meshheading:10651647-Cricetinae,
pubmed-meshheading:10651647-Cysteine Endopeptidases,
pubmed-meshheading:10651647-Cysteine Proteinase Inhibitors,
pubmed-meshheading:10651647-Endopeptidases,
pubmed-meshheading:10651647-Endoplasmic Reticulum,
pubmed-meshheading:10651647-Humans,
pubmed-meshheading:10651647-Hydrolysis,
pubmed-meshheading:10651647-Intracellular Fluid,
pubmed-meshheading:10651647-Leupeptins,
pubmed-meshheading:10651647-Multienzyme Complexes,
pubmed-meshheading:10651647-Neurons,
pubmed-meshheading:10651647-Peptide Fragments,
pubmed-meshheading:10651647-Proteasome Endopeptidase Complex,
pubmed-meshheading:10651647-Recombinant Fusion Proteins,
pubmed-meshheading:10651647-Tumor Cells, Cultured
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pubmed:year |
2000
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pubmed:articleTitle |
A distinct ER/IC gamma-secretase competes with the proteasome for cleavage of APP.
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pubmed:affiliation |
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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