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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.
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Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.

机译：肝X受体激动剂治疗可改善APP23小鼠中高脂饮食引起的淀粉样蛋白病理和记忆障碍。

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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 Abeta and soluble Abeta 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 Abeta degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Abeta levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Abeta 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 Abeta deposition and facilitating its clearance.
机译：高脂饮食和某些饮食习惯与偶发性阿尔茨海默氏病（AD）的发生率较高和认知能力下降有关。然而，尚未提出任何具体疗法来改善高脂肪/高胆固醇水平对认知和淀粉样蛋白病理学的负面影响。在这里，我们显示在9个月大的APP23小鼠中，提供4个月的高脂/高胆固醇（HF）饮食会加剧通过行为，形态学和生化分析评估的AD表型。为了检查肝X受体（LXR）配体的治疗潜力，向APP23小鼠喂食了补充有合成LXR激动剂T0901317（T0）的HF日粮。我们的结果表明，LXR配体处理可显着减少在莫里斯水迷宫的获取和保留阶段观察到的记忆缺陷。此外，T0对认知的影响与AD样的形态和生化参数相关。我们发现淀粉样蛋白斑块负荷，不溶性Abe​​ta和可溶性Abe​​ta寡聚体显着降低。初级神经胶质细胞的体外实验表明，Abca1对ApoE的正确脂化至关重要，并介导了T0对小胶质细胞对Abeta降解的影响。在清醒自由运动的小鼠上进行的微透析实验表明，T0降低了海马组织液中Abeta的水平，支持了这种治疗增加Abeta清除率的结论。最终提供的数据表明，在代谢挑战的情况下，LXR激活通过减弱Abeta沉积并促进其清除而对AD表型进展具有关键影响。

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