Expression profiling in APP23 mouse brain: inhibition of Aβ amyloidosis and inflammation in response to LXR agonist treatment
Open accessAbstract
BACKGROUND: Recent studies demonstrate that in addition to its modulatory effect on APP processing, in vivo application of Liver X Receptor agonist T0901317 (T0) to APP transgenic and non-transgenic mice decreases the level of Abeta42. Moreover, in young Tg2576 mice T0 completely reversed contextual memory deficits. Compared to other tissues, the regulatory functions of LXRs in brain remain largely unexplored and our knowledge so far is limited to the cholesterol transporters and apoE. In this study we applied T0 to APP23 mice for various times and examined gene and protein expression. We also performed a series of experiments with primary brain cells derived from wild type and LXR knockout mice subjected to various LXR agonist treatments and inflammatory stimuli. RESULTS: We demonstrate an upregulation of genes related to lipid metabolism/transport, metabolism of xenobiotics and detoxification. Downregulated genes are involved in immune response and inflammation, cell death and apoptosis. Additional treatment experiments demonstrated an increase of soluble apolipoproteins E and A-I and a decrease of insoluble Abeta. In primary LXRwt but not in LXRalpha-/-beta-/- microglia and astrocytes LXR agonists suppressed the inflammatory response induced by LPS or fibrillar Abeta. CONCLUSION: The results show that LXR agonists could alleviate AD pathology by acting on amyloid deposition and brain inflammation. An increased understanding of the LXR controlled regulation of Abeta aggregation and clearance systems will lead to the development of more specific and powerful agonists targeting LXR for the treatment of AD.
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Lefterov et al. (2007) observed that drug effects wear off with time of treatment.
“However, Lefterov et al. (2007) observed that drug effects wear off with time of treatment.”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Lefterov et al., 2007
The Results section on pro-inflammatory genes reports the opposite pattern for that outcome: 24 hours of T0 treatment had no effect on the genes examined, whereas 25 days significantly reduced expression of IL-1β, IL-6, and TNFα. The paper does not report those drug effects wearing off with treatment time. (LLM, conf=0.87)
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Experimental — accuracy not yet measuredLXR agonist treatment alleviates AD-like pathology in mouse models of amyloidosis, possibly by inducing Abca1 expression.
“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 [46]
The paradoxical increase in soluble Aβ was not observed in young APP23 mice or in control or aged APP23 mice after long-term TO901317 treatment.
“was not observed either in young APP23 mice (Lefterov et al., 2007) or in control or aged APP23 mice (this study) after long-term TO901317 treatment”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Lefterov et al., 2007
Long-term treatment with TO901317 in 6-month-old APP23 mice did not affect soluble Aβ.
“However, long-term treatment with TO901317 in 6-month-old APP23 mice did not have an effect on soluble A (Lefterov et al., 2007)”
From Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis (2011) · cites this paper as Lefterov et al., 2007
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Self-citation
- Authors
- Lefterov, I., Bookout, A., Wang, Z., Staufenbiel, M., Mangelsdorf, D., & Koldamova, R.
- Affiliations
- University of Pittsburgh (US)
- Howard Hughes Medical Institute (US)
- Novartis Institutes for BioMedical Research (CH)
- Corresponding author
- Lefterov, Iliya
- Koldamova, Radosveta
- Venue
- Molecular Neurodegeneration
- Published
- 2007
- Volume
- 2
- Issue
- 1
- Pages
- 20
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC2214725
- OpenAlex
- W2149217753
- Cited by
- 89
- References
- 61
- Citations by year
- 2025: 6 · 2024: 1 · 2023: 9 · 2022: 4 · 2021: 8 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 6 · 2014: 3 · 2013: 10 · 2012: 4
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- Alzheimer's Association
- National Institute on Aging (R03AG028794, R03AG023304)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- liver X receptor agonist, T0901317, APP23 mice, Alzheimer's disease, amyloid-beta, amyloid-beta 42, neuroinflammation, gene expression profiling, lipid metabolism, xenobiotic metabolism, apolipoprotein E, apolipoprotein A-I, microglia, astrocytes, lipopolysaccharide, fibrillar amyloid-beta
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