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The Liver X Receptor Ligand T0901317 Decreases Amyloid β Production in Vitro and in a Mouse Model of Alzheimer's Disease
Open accessAbstract
Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid beta (Abeta) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on Abeta production in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concentration-dependent decrease in Abeta secretion, and this effect was increased by the addition of apolipoprotein A-I. The inhibition of Abeta production by T0901317 was cell-type specific, being more prominent in primary neurons than in non-neuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Abeta than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Abeta generation. T0901317 treatment of 11-week-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of soluble APP (sAPP)beta- to sAPPalpha-cleavage products. Most importantly, the treatment caused a statistically significant reduction in the levels of soluble Abeta40 and of Abeta42 in the brain these mice. Our experiments demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.
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“dosing of APP transgenic mice with LXR agonists, which increase murine CNS apoE levels, also decrease A levels (Koldamova et al., 2005;Burns et al., 2006;Riddell et al., 2007).”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Koldamova et al., 2005
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“LXR agonist treatment alleviates AD-like pathology in mouse models of amyloidosis, possibly by inducing Abca1 expression (29, 43–48).”
From The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis (2015) · cites this paper as [45]
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“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 [63]
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“ABCA1 gene ablation in mice decreased APOE lipidation and levels and increased Aβ accumulation in APP transgenic mouse models.”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [63]
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“LXR agonists have been shown to decrease A deposition in the brain while modestly increasing apoE expression (Koldamova et al., 2005;Zelcer et al., 2007;Fitz et al., 2010).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Koldamova et al., 2005
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“Interestingly, several genes expressed in the liver including liver X receptors (LXRs) have been suggested as potential therapeutic targets for AD [189–191].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [191]
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Metadata
- Authors
- Koldamova, R. P., Lefterov, I. M., Staufenbiel, M., Wolfe, D., Huang, S., Glorioso, J. C., Walter, M., Roth, M. G., & Lazo, J. S.
- Affiliations
- University of Pittsburgh (US)
- Novartis Institutes for BioMedical Research (CH)
- University of Münster (DE)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Koldamova, Radosveta P.
- Lefterov, Iliya M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-02
- Volume
- 280
- Issue
- 6
- Pages
- 4079-4088
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1996457468
- Cited by
- 279
- References
- 55
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 4 · 2023: 5 · 2022: 10 · 2021: 11 · 2020: 12 · 2019: 8 · 2018: 6 · 2017: 11 · 2016: 13 · 2015: 15 · 2014: 17 · 2013: 22 · 2012: 15
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- University of Pittsburgh
- National Institutes of Health
- National Institute on Aging (AG 18558, AG 23304, R03AG023304)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- liver X receptor, T0901317, amyloid-beta, Alzheimer's disease, ABCA1, oxysterols, APP processing, APP23 transgenic mice, apolipoprotein A-I, soluble APP alpha, cell type specificity, LXR ligands
- MeSH terms
- Liver X Receptors, Benzenesulfonamides, Alzheimer Disease, Animals, Anticholesteremic Agents, Brain, Cloning, Molecular, Disease Models, Animal, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Fibroblasts, Fluorocarbons, Humans, Hydrocarbons, Fluorinated, Ligands, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Protein Binding, Sulfonamides, Time Factors, Transcription, Genetic, Transfection, Blotting, Western, Up-Regulation, Amyloid beta-Protein Precursor, Apolipoprotein A-I, DNA, Complementary, Simplexvirus, Receptors, Cytoplasmic and Nuclear, Immunoprecipitation, Mice, Orphan Nuclear Receptors
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