Department of Neurology, University of Bonn, 53127 Bonn, Germany.
J Neurosci. 2011 May 11;31(19):7049-59. doi: 10.1523/JNEUROSCI.6546-10.2011.
Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-β (Aβ) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble Aβ levels in the treated APP23 mice were reduced by 80% and 40%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by Aβ disposal. Despite the profound effect on Aβ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar Aβ. Conditioned medium from TO901317-treated ApoE(-/-) or LXRα(-/-) astrocytes did not increase phagocytosis of Aβ. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and Aβ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXRα and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXRα activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar Aβ in response to treatment with TO901317.
肝 X 受体 (LXRs) 调节免疫细胞功能和胆固醇代谢，这两个因素都与阿尔茨海默病 (AD) 密切相关。为了研究 LXR 长期激活在 AD 模型中淀粉样β (Aβ) 肽沉积中的治疗潜力，用 LXR 激动剂 TO901317 处理 13 月龄、载有淀粉样斑块的 APP23 小鼠。尸检分析表明，TO901317 能有效地穿过血脑屏障。与未处理的动物相比，用 TO901317 处理的 APP23 小鼠的不溶性和可溶性 Aβ 水平分别降低了 80%和 40%。然而，该化合物对 APP 处理几乎没有影响，这表明观察到的效应是通过 Aβ 处置介导的。尽管对 Aβ 水平有深远影响，但莫利斯水迷宫中的空间学习仅略有改善。ABCA1（ATP 结合盒转运蛋白 1）和载脂蛋白 E（ApoE）蛋白水平增加，主要定位于星形胶质细胞。使用原代小胶质细胞的实验表明，暴露于 TO901317 的原代星形胶质细胞的培养基刺激纤维状 Aβ的吞噬作用。来自 TO901317 处理的 ApoE(-/-)或 LXRα(-/-)星形胶质细胞的条件培养基不会增加 Aβ 的吞噬作用。在 APP23 小鼠中，TO901317 的长期治疗强烈增加了小胶质细胞和 Aβ 斑块的关联。用 TO901317 短期治疗 APP/PS1 小鼠也增加了这种关联，这依赖于 LXRα 的存在，并伴有 ApoE 脂质化增加。总之，这些数据表明，星形胶质细胞 LXRα 的激活和随后星形胶质细胞释放 ApoE 对于小胶质细胞在 TO901317 治疗下清除纤维状 Aβ的能力至关重要。
