Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons

J Alzheimers Dis. 2009;16(1):121-31. doi: 10.3233/JAD-2009-0944.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters / biosynthesis*
  • ATP-Binding Cassette Transporters / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / genetics
  • Animals
  • Apolipoproteins E / genetics
  • Blotting, Western
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • DNA-Binding Proteins / drug effects
  • Humans
  • Hydroxycholesterols / pharmacology*
  • Liver X Receptors
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Orphan Nuclear Receptors
  • Peptide Fragments / genetics
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • ABCA1 protein, human
  • ABCG1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • Amyloid beta-Peptides
  • Apolipoproteins E
  • DNA-Binding Proteins
  • Hydroxycholesterols
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Peptide Fragments
  • Receptors, Cytoplasmic and Nuclear
  • amyloid beta-protein (1-42)
  • 27-hydroxycholesterol
  • Amyloid Precursor Protein Secretases