Affiliations: [a] Prince of Wales Medical Research Institute, Randwick, NSW, Australia | [b] Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, VIC, Australia | [c] Department of Pathology, University of Melbourne, VIC, Australia | [d] The Mental Health Research Institute of Victoria, Parkville, VIC, Australia | [e] Centre for Immunology, St. Vincent's Hospital, Sydney, NSW, Australia | [f] School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
Correspondence:
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Corresponding author: Dr Scott Kim, Prince of Wales Medical Research Institute, Barker St., Randwick, NSW 2031, Australia. Tel.: +61 2 939 91084; Fax.: +61 2 939 91005, E-mail: w.kim@unsw.edu.au.
Abstract: Cholesterol is an integral component of neuronal membranes and recent evidence has shown that it regulates amyloid-β protein precursor processing to form amyloid-β 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-β peptide generation, however, this has not been investigated in primary human neurons. Here we show that 27OHC significantly reduced amyloid-β peptide detected in cell culture supernatants from primary human neurons. We also show that 27OHC does not affect α-, β- or γ-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-β peptide levels is potentially due to its action as an LXR ligand.
Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, ATP-binding cassette transporters, 27-hydroxycholesterol, primary human neurons
