The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer's disease
The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer's disease
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DOI：
10.1016/j.mcn.2007.01.011
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Jacobsen, J. Steve
中科院分区：
文献类型：
--
作者：
Riddell, David R.;Zhou, Hua;Jacobsen, J. Steve
最近的研究表明，细胞内胆固醇水平可以调节淀粉样前体蛋白向 Aβ 肽的加工。此外，富含胆固醇的含apoE脂蛋白也可能促进Aβ清除。肝脏 X 受体 (LXR) 激动剂转录诱导参与细胞内脂质流出和运输的基因，包括 apoE。因此，LXR 激动剂具有抑制 APP 加工和促进 Aβ 清除的潜力。在这里，我们发现 LXR 激动剂 TO901317 增加了 APP 转基因小鼠的海马 ABCA1 和 apoE，并降低了 Aβ 42 水平。 TO901317 对 A beta 40、全长 APP 或 APP 加工产品的水平没有显着影响。接下来，我们检查了 TO901317 在情境恐惧调节范式中的效果； TO901317 完全逆转了这些小鼠的情境记忆缺陷。这些数据表明，LXR 激动剂并不直接抑制 APP 加工，而是促进 A beta 42 的清除，可能代表阿尔茨海默氏病的一种新治疗方法。 (c) 2007 Elsevier Inc. 保留所有权利。
Recent studies show that intracellular cholesterol levels can modulate the processing of amyloid precursor protein to A beta peptide. Moreover, cholesterol-rich apoE-containing lipoproteins may also promote A beta clearance. Agonists of the liver X receptor (LXR) transcriptionally induce genes involved in intracellular lipid efflux and transport, including apoE. Thus, LXR agonists have the potential to both inhibit APP processing and promote A beta clearance. Here we show that LXR agonist, TO901317, increased hippocampal ABCA1 and apoE and decreased A beta 42 levels in APP transgenic mice. TO901317 had no significant effects on levels of A beta 40, full length APP, or the APP processing products. Next, we examined the effects of TO901317 in the contextual fear conditioning paradigm; TO901317 completely reversed the contextual memory deficit in these mice. These data demonstrate that LXR agonists do not directly inhibit APP processing but rather facilitate the clearance of A beta 42 and may represent a novel therapeutic approach to Alzheimer's disease. (c) 2007 Elsevier Inc. All rights reserved.