Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons.
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.
Kim
Woojin Scott
WS
Prince of Wales Medical Research Institute, Randwick, NSW, Australia. w.kim@unsw.edu.au
Chan
Sharon L
SL
Hill
Andrew F
AF
Guillemin
Gilles J
GJ
Garner
Brett
B
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D015153:Blotting, Western; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D000071518:Liver X Receptors; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D018160:Receptors, Cytoplasmic and Nuclear; C075222:amyloid beta-protein (1-42); C076996:27-hydroxycholesterol; D053829:Amyloid Precursor Protein Secretases