Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment.
Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment.
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DOI：
10.1186/1750-1326-2-20
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发表时间：
2007-10-22
影响因子：
15.1
通讯作者：
Koldamova R
中科院分区：
文献类型：
--
作者：
Lefterov I;Bookout A;Wang Z;Staufenbiel M;Mangelsdorf D;Koldamova R
最近的研究表明，除了对APP加工的调节作用外，肝脏X受体激动剂T0901317（T0）在体内应用于APP转基因和非转基因小鼠可降低Aβ42的水平。此外，在年轻的Tg 2576小鼠中，T0完全逆转了上下文记忆缺陷。与其他组织相比，LXR在脑中的调节功能在很大程度上尚未被探索，我们的知识目前仅限于胆固醇转运蛋白和apoE。在这项研究中，我们将T0应用于APP 23小鼠不同的时间，并检查基因和蛋白质表达。我们还用来源于野生型和LXR敲除小鼠的原代脑细胞进行了一系列实验，这些小鼠经历了各种LXR激动剂治疗和炎症刺激。我们证明了与脂质代谢/运输，异生物质代谢和解毒相关的基因的上调。下调的基因参与免疫应答和炎症、细胞死亡和凋亡。其他处理实验表明可溶性载脂蛋白E和A-I增加，不溶性Aβ减少。在原发性LXR wt中，而不是在LXRα-/-β-/-小胶质细胞和星形胶质细胞中，LXR激动剂抑制LPS或纤维状Aβ诱导的炎症反应。结果表明，LXR激动剂可以通过作用于淀粉样蛋白沉积和脑炎症来减轻AD病理。对LXR控制的Aβ聚集和清除系统的调节的更多理解将导致开发更特异性和更强大的靶向LXR的激动剂用于治疗AD。
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 Aβ42. 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. 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 Aβ. In primary LXRwt but not in LXRα-/-β-/- microglia and astrocytes LXR agonists suppressed the inflammatory response induced by LPS or fibrillar Aβ. 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 Aβ 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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影响因子：
4.8
作者：
Horvath, AJ;Irving, JA;Whisstock, JC
通讯作者：
Whisstock, JC
DOI：
10.1161/01.atv.0000227472.70734.ad
发表时间：
2006-08-01
影响因子：
8.7
作者：
Han, Chang Yeop;Chiba, Tsuyoshi;Chait, Alan
通讯作者：
Chait, Alan
影响因子：
2.1
作者：
Koldamova, Radosveta;Lefterov, Iliya
通讯作者：
Lefterov, Iliya
影响因子：
82.9
作者：
Koistinaho, M;Lin, SZ;Paul, SM
通讯作者：
Paul, SM
DOI：
10.1124/jpet.103.064535
发表时间：
2004-06-01
影响因子：
3.5
作者：
Beyer, TP;Schmidt, RJ;Cao, GQ
通讯作者：
Cao, GQ