Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice
Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice
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DOI：
10.1523/jneurosci.1051-10.2010
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发表时间：
2010-05-19
影响因子：
5.3
通讯作者：
Koldamova, Radosveta
中科院分区：
文献类型：
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作者：
Fitz, Nicholas F.;Cronican, Andrea;Koldamova, Radosveta
高脂肪饮食和某些饮食模式与散发性阿尔茨海默病（AD）和认知能力下降的发病率较高有关。然而，没有具体的治疗已经提出来改善高脂肪/高胆固醇水平对认知和淀粉样蛋白病理的负面影响。在这里，我们表明，在9个月大的APP 23小鼠，高脂肪/高胆固醇（HF）的饮食提供了4个月恶化的AD表型的行为，形态学和生化测定评估。为了检查肝脏X受体（LXR）配体的治疗潜力，向APP 23小鼠饲喂补充有合成LXR激动剂T0901317的HF饮食（T0）。我们的研究结果表明，LXR配体治疗引起的Morris水迷宫的采集和保留阶段期间观察到的记忆缺陷显着减少。此外，T0对认知的影响与AD样形态学和生化参数相关。我们发现淀粉样斑块负荷、不溶性A β和可溶性A β寡聚体显著减少。原代神经胶质细胞的体外实验表明，Abca 1对ApoE的适当脂化至关重要，并介导T0对小胶质细胞A β降解的影响。对清醒的自由活动小鼠进行的微透析实验表明，T0降低了海马间质液中的A β水平，支持该处理增加A β清除率的结论。提供的数据最终表明，在代谢挑战的背景下，LXR激活通过减弱A β沉积并促进其清除对AD表型进展具有关键作用。
High-fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9-month-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological, and biochemical assays. To examine the therapeutic potential of liver X receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris water maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble A beta and soluble A beta oligomers. In vitro experiments with primary glia demonstrate that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on A beta degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased A beta levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases A beta clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating A beta deposition and facilitating its clearance.