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22R-hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol
Radosveta P Koldamova1, Iliya M Lefterov, Milos D Ikonomovic
1Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. radak@pitt.edu
The Journal of Biological Chemistry
|January 28, 2003
Summary
The ATP-binding cassette transporter A1 (ABCA1) regulates cholesterol efflux in the brain. Activating ABCA1 with specific ligands reduces amyloid-beta production, offering a potential strategy for Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- The ATP-binding cassette transporter A1 (ABCA1) is crucial for cholesterol metabolism and high-density lipoprotein (HDL) regulation.
- ABCA1 is highly expressed in specific neurons within the adult rat brain, including the hypothalamus, thalamus, amygdala, basal forebrain, and hippocampus.
- Cholesterol homeostasis is vital for central nervous system (CNS) function and neurodegeneration, prompting investigation into ABCA1's role in brain cells.
Purpose of the Study:
- To investigate ABCA1 expression and function in primary rat brain cell cultures (neurons, astrocytes, microglia).
- To determine the effect of nuclear hormone receptor ligands on ABCA1 expression and cholesterol efflux.
- To evaluate the impact of ABCA1 modulation on amyloid precursor protein (APP) processing and amyloid-beta (Aβ) production.
Main Methods:
- Primary cultures of embryonic rat neurons, astrocytes, and microglia were used.
- ABCA1 mRNA and protein levels were analyzed after treatment with oxysterols and 9-cis-retinoic acid (ligands for LXR and RXR, respectively).
- Cholesterol efflux mediated by apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE) was measured.
- APP C-terminal fragments (CTFs) stability and Aβ production were assessed in cells overexpressing a Swedish APP variant.
Main Results:
- Basal ABCA1 expression in neurons and glia was significantly upregulated by oxysterols and 9-cis-retinoic acid.
- Ligand-induced ABCA1 expression enhanced apoA-I- and apoE-mediated cholesterol efflux from both neuronal and glial cells.
- In cells expressing Swedish APP, these ligands decreased cellular cholesterol content by promoting efflux.
- Treatment with ligands and/or apoA-I reduced APP CTF stability and decreased Aβ production.
Conclusions:
- ABCA1 expression and function in brain cells can be modulated by nuclear hormone receptor ligands.
- Modulating ABCA1 enhances cholesterol efflux and reduces amyloid-beta production, suggesting a therapeutic target for neurodegenerative diseases.
- 22R-hydroxycholesterol, by influencing ABCA1, may offer a novel strategy to reduce brain amyloid burden.