Abstract
Processing of the amyloid-β (Aβ) precursor protein (APP) has been extensively studied since it leads to production of Aβ peptides. Toxic forms of Aβ aggregates are considered the cause of Alzheimer's disease (AD). On the other end, BRI2 is implicated in APP processing and Aβ production. We have investigated the precise mechanism by which BRI2 modulates APP cleavages and have found that BRI2 forms a mature BRI2 polypeptide that is transported to the plasma membrane and endosomes where it interacts with mature APP. Notably, immature forms of APP and BRI2 fail to interact. Mature BRI2 inhibits APP processing by α-, β- and γ-secretases on the plasma membrane and in endocytic compartments. Thus, BRI2 is a specific inhibitor that reduces secretases' access to APP in the intracellular compartments where APP is normally processed.
Copyright © 2009. Published by Elsevier Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Alzheimer Disease / enzymology
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Amyloid Precursor Protein Secretases / antagonists & inhibitors
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Protein Precursor / physiology*
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Animals
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Cell Membrane / enzymology
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Cell Membrane / genetics
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Cell Membrane / metabolism*
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Fibroblasts / cytology
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Fibroblasts / metabolism
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HEK293 Cells
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HeLa Cells
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Humans
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Membrane Glycoproteins / biosynthesis*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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Mice
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Protein Processing, Post-Translational*
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Transport Vesicles / enzymology
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Transport Vesicles / genetics
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Transport Vesicles / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Amyloid beta-Protein Precursor
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ITM2B protein, human
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Membrane Glycoproteins
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Amyloid Precursor Protein Secretases