Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide Secretion
Open accessAbstract
A hallmark of Alzheimer's disease is the deposition of plaques of amyloid beta peptide (Abeta) in the brain. Abeta is thought to be formed from the amyloid precursor protein (APP) in cholesterol-enriched membrane rafts, and cellular cholesterol depletion decreases Abeta formation. The liver X receptors (LXR) play a key role in regulating genes that control cellular cholesterol efflux and membrane composition and are widely expressed in cells of the central nervous system. We show that treatment of APP-expressing cells with LXR activators reduces the formation of Abeta. LXR activation resulted in increased levels of the ATP-binding cassette transporter A1 (ABCA1) and stearoyl CoA desaturase, and expression of these genes individually decreased formation of Abeta. Expression of ABCA1 led to both decreased beta-cleavage product of APPSw (i.e. C99 peptide) and reduced gamma-secretase-cleavage of C99 peptide. Remarkably, these effects of ABCA1 on APP processing were independent of cellular lipid efflux. LXR and ABCA1-induced changes in membrane lipid organization had favorable effects on processing of APP, suggesting a new approach to the treatment of Alzheimer's disease.
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ABCA1 decreases Aβ secretion by inhibiting BACE1-mediated APP cleavage without affecting BACE1 expression in neuronal cells.
“We and others previously demonstrated that ABCA1 decreases A secretion by inhibiting BACE1-mediated APP cleavage without affecting BACE1 expression in neuronal cells (Sun et al., 2003;Kim et al., 2012).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Sun et al., 2003
In vitro evidence supports a critical role of ABCA1 in Aβ production.
“Furthermore, several lines of in vitro evidence support the critical role of ABCA1 in A production, although how ABCA1 regulates A production remains to be clarified (Koldamova et al., 2003;Sun et al., 2003;Kim et al., 2007).”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Sun et al., 2003
ABCA1 induction decreases Aβ levels in cells by inhibiting both β- and γ-cleavage of APP.
“Koldamova et al. and Sun et al. reported that ABCA1 induction decreases Aβ levels in cells by inhibiting both β- and γ-cleavage of APP [62-64].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [64]
ABCA1 induction by LXR agonist decreases Aβ production in various cell lines.
“ABCA1 induction by liver X receptor (LXR) agonist decreased Aβ production in various cell lines (Kim et al., 2007; Koldamova et al., 2003; Sun et al., 2003).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Sun et al., 2003
Most studies demonstrated that ABCA1 induction decreases the levels of Aβ and CTFβ.
“Most of studies demonstrated that ABCA1 induction decreases the levels of Aβ and CTFβ (Kim et al., 2007; Koldamova et al., 2003; Sun et al., 2003).”
From miR-106b impairs cholesterol efflux and increases Aβ levels by repressing ABCA1 expression (2012) · cites this paper as Sun et al., 2003
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References 42 · Cited by 179
- Authors
- Sun, Y., Yao, J., Kim, T.-W., & Tall, A. R.
- Affiliations
- Columbia University (US)
- Corresponding author
- Tall, Alan R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-07
- Volume
- 278
- Issue
- 30
- Pages
- 27688-27694
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2028195118
- Cited by
- 179
- References
- 42
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 2 · 2019: 5 · 2017: 4 · 2016: 2 · 2015: 2 · 2014: 13 · 2013: 10 · 2012: 9
- FWCI
- 8.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag018026-04)
- National Institute on Aging (AG18026)
- National Heart, Lung, and Blood Institute (HL22682, P01HL054591, HL 54591)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- liver X receptor, amyloid-beta, Alzheimer's disease, APP processing, ABCA1, stearoyl-CoA desaturase, cholesterol, lipid rafts, gamma-secretase, cholesterol efflux
- MeSH terms
- Liver X Receptors, Alzheimer Disease, Animals, Apolipoproteins E, Cell Line, Cholesterol, DNA-Binding Proteins, Humans, Neurons, Peptides, Precipitin Tests, Stearoyl-CoA Desaturase, Tumor Cells, Cultured, Immunoblotting, Blotting, Western, Amyloid beta-Peptides, Receptors, Cytoplasmic and Nuclear, ATP-Binding Cassette Transporters, Protein Isoforms, Lipid Metabolism, Mice, Orphan Nuclear Receptors, ATP Binding Cassette Transporter 1
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