Expression profiling in APP23 mouse brain: inhibition of Aß amyloidosis and inflammation in response to LXR agonist treatment
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Lefterov, Iliya, Bookout, Angie, Wang, Zhu, Staufenbiel, Matthias, Mangelsdorf, David and Koldamova, Radosveta (2007) Expression profiling in APP23 mouse brain: inhibition of Aß amyloidosis and inflammation in response to LXR agonist treatment. Molecular Neurodegeneration, 2 (1). p. 20. ISSN 1750-1326
Abstract
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 Aß42. 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 Aß. In primary LXRwt but not in LXRa-/-ß-/- microglia and astrocytes LXR agonists suppressed the inflammatory response induced by LPS or fibrillar Aß.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 Aß 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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| Additional Information: | free final full text version available at publisher's official URL and at PubMedCentral; author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF may be used |
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| Date Deposited: | 13 Oct 2015 13:17 |
| Last Modified: | 13 Oct 2015 13:17 |
| URI: | https://oak.novartis.com/id/eprint/217 |