Abstract
Cholesterol is an integral component of neuronal membranes and recent evidence has shown that it regulates amyloid-beta protein precursor processing to form amyloid-beta peptides, which are a major constituent of cerebral amyloid plaques associated with Alzheimer's disease. 27-Hydroxycholesterol (27OHC) is synthesized from cholesterol via sterol 27-hydroxylase (CYP27A1) in the brain and, unlike cholesterol, can cross into the brain through the blood brain barrier from the circulation. Previous studies point toward a potential role for 27OHC in the regulation of neuronal amyloid-beta peptide generation, however, this has not been investigated in primary human neurons. Here we show that 27OHC significantly reduced amyloid-beta peptide detected in cell culture supernatants from primary human neurons. We also show that 27OHC does not affect alpha-, beta- or gamma-secretase activity but does upregulate the liver X receptor (LXR) responsive genes ABCA1, ABCG1 and APOE. These data suggest that 27OHC-mediated reduction in extracellular amyloid-beta peptide levels is potentially due to its action as an LXR ligand.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily G, Member 1
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ATP-Binding Cassette Transporters / biosynthesis*
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ATP-Binding Cassette Transporters / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / biosynthesis*
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Amyloid beta-Peptides / genetics
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Animals
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Apolipoproteins E / genetics
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Blotting, Western
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CHO Cells
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Cells, Cultured
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Cricetinae
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Cricetulus
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DNA-Binding Proteins / drug effects
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Humans
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Hydroxycholesterols / pharmacology*
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Liver X Receptors
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Neurons / drug effects*
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Neurons / metabolism*
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Orphan Nuclear Receptors
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Peptide Fragments / genetics
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Receptors, Cytoplasmic and Nuclear / drug effects
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Reverse Transcriptase Polymerase Chain Reaction
Substances
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ABCA1 protein, human
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ABCG1 protein, human
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily G, Member 1
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ATP-Binding Cassette Transporters
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Amyloid beta-Peptides
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Apolipoproteins E
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DNA-Binding Proteins
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Hydroxycholesterols
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Liver X Receptors
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Orphan Nuclear Receptors
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Peptide Fragments
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Receptors, Cytoplasmic and Nuclear
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amyloid beta-protein (1-42)
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27-hydroxycholesterol
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Amyloid Precursor Protein Secretases