Abstract
Clinical, pharmacological, biochemical, and genetic evidence support the notion that alteration of cholesterol homeostasis strongly predisposes to Alzheimer disease (AD). The ATP-binding cassette transporter-2 (Abca2), which plays a role in intracellular sterol trafficking, has been genetically linked to AD. It is unclear how these two processes are related. Here we demonstrate that down-regulation of Abca2 in mammalian cells leads to decreased amyloid-β (Aβ) generation. In vitro studies revealed altered γ-secretase complex formation in Abca2 knock-out cells due to the altered levels, post-translational modification, and subcellular localization of Nicastrin. Reduced Abca2 levels in mammalian cells in vitro, in Drosophila melanogaster and in mice resulted in altered γ-secretase processing of APP, and thus Aβ generation, without affecting Notch cleavage.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / biosynthesis*
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Down-Regulation / genetics
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster
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HEK293 Cells
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Humans
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Rats
Substances
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ABCA2 protein, human
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APP protein, human
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ATP-Binding Cassette Transporters
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Abca2 protein, mouse
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Abca2 protein, rat
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Amyloid beta-Protein Precursor
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Drosophila Proteins
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Membrane Glycoproteins
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Nerve Tissue Proteins
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nicastrin protein
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Amyloid Precursor Protein Secretases