Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors
Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors
复制标题
DOI：
10.1073/pnas.0701096104
复制
发表时间：
2007-06-19
影响因子：
11.1
通讯作者：
Tontonoz, Peter
中科院分区：
文献类型：
--
作者：
Zelcer, Noam;Khanlou, Negar;Tontonoz, Peter
阿尔茨海默病（AD）是一种年龄依赖性神经退行性疾病，导致进行性认知障碍。AD的发生和发展与胆固醇代谢和炎症有关，这些过程可以通过肝脏x受体（LXR）进行调节。我们在这里表明，内源性LXR信号影响AD相关病理的发展。APP/PS1转基因小鼠中Lxr α或Lxr β的遗传缺失导致淀粉样斑块负荷增加。LXR调节大脑中关键胆固醇稳态基因的基础和诱导表达，并作为炎症基因表达的有效抑制剂。LXR的配体激活以受体依赖性方式减弱原代混合神经胶质培养物对纤维状淀粉样蛋白P肽（fA β）的炎症反应。此外，LXR促进小胶质细胞在炎症环境中维持fA β刺激的吞噬作用的能力。这些结果鉴定了内源性LXR信号传导作为小鼠中AD发病机制的重要决定因素。我们认为LXRs可能是治疗AD的易处理靶点，因为它们能够调节脑中脂质代谢和炎症基因表达。
Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxr alpha or Lxr beta in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid P peptide (fA beta) in a receptor-dependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fA beta-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.