Abstract
Recent reports suggest that some commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) unexpectedly shift the cleavage products of amyloid precursor protein (APP) to shorter, less fibrillogenic forms, although the underlying mechanism remains unknown. We now demonstrate, using a fluorescence resonance energy transfer method, that Abeta(42)-lowering NSAIDs specifically affect the proximity between APP and presenilin 1 and alter presenilin 1 conformation both in vitro and in vivo, suggesting a novel allosteric mechanism of action.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Aspartic Acid Endopeptidases
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CHO Cells
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Carrier Proteins / metabolism*
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Cricetinae
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Cricetulus
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Dose-Response Relationship, Drug
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Endopeptidases / metabolism*
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Fluorescence Resonance Energy Transfer
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Membrane Proteins / chemistry*
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Mice
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Mice, Transgenic
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Models, Molecular*
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Peptide Fragments / metabolism*
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Presenilin-1
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Protease Nexins
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Protein Conformation / drug effects
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Receptors, Cell Surface
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Anti-Inflammatory Agents, Non-Steroidal
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Carrier Proteins
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Membrane Proteins
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Peptide Fragments
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Presenilin-1
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Protease Nexins
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Receptors, Cell Surface
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amyloid beta-protein (17-42)
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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Bace1 protein, mouse