Abstract
Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and gamma-secretase, plays a crucial role in the pathogenesis of Alzheimer disease. Much has been discovered on the properties of these proteases; however, regulatory mechanisms of enzyme-substrate interaction in neurons and their involvement in pathological changes are still not fully understood. It is mainly because of the membrane-associated cleavage of these proteases and the lack of information on new substrates processed in a similar way to APP. Here, using RNA interference-mediated BACE1 knockdown, mouse embryonic fibroblasts that are deficient in either BACE1 or presenilins, and BACE1-deficient mouse brain, we show clear evidence that beta subunits of voltage-gated sodium channels are sequentially processed by BACE1 and gamma-secretase. These results may provide new insights into the underlying pathology of Alzheimer disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / metabolism
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Amino Acid Sequence
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Amyloid Precursor Protein Secretases
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Amyloid beta-Protein Precursor / chemistry
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Animals
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Aspartic Acid Endopeptidases
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Binding Sites
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Blotting, Western
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Brain / metabolism
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Cell Line
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Cell Membrane / metabolism
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Cells, Cultured
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Detergents / pharmacology
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Endopeptidases / chemistry*
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Endopeptidases / metabolism
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Fibroblasts / metabolism
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Genetic Vectors
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Fluorescence
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Molecular Sequence Data
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Neurons / metabolism
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Phosphoric Monoester Hydrolases / metabolism
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Protein Binding
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Protein Structure, Tertiary
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RNA Interference
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Sequence Homology, Amino Acid
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Transfection
Substances
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Amyloid beta-Protein Precursor
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Detergents
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Phosphoric Monoester Hydrolases
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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, human
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Bace1 protein, mouse