Non-alcoholic fatty liver disease induces signs of Alzheimer's disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model.
Non-alcoholic fatty liver disease induces signs of Alzheimer's disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model.
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DOI：
10.1186/s12974-015-0467-5
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发表时间：
2016-01-05
影响因子：
9.3
通讯作者：
Bynoe MS
中科院分区：
文献类型：
--
作者：
Kim DG;Krenz A;Toussaint LE;Maurer KJ;Robinson SA;Yan A;Torres L;Bynoe MS
非酒精性脂肪性肝病（NAFLD）是一种慢性肝病，困扰着约三分之一的世界人口和30%的美国人口。它是由高脂饮食引起的，其特征是肝脏炎症和随后的肝脏病理学。众所周知，肥胖和高脂肪饮食会增加患阿尔茨海默病（AD）的风险。在这里，我们研究了NAFLD诱导的肝脏炎症在AD发病机制中的作用。WT和APP-Tg小鼠用标准饮食（SD）或高脂肪饮食（HFD）喂养2、5个月或1年以诱导NAFLD。另一组APP-Tg小鼠在2个月后从HFD中取出，并放回SD 3个月。在急性期NAFLD期间，WT和APP-Tg小鼠发生了显著的肝脏炎症和病理学，其与脑中活化的小胶质细胞数量增加、炎性细胞因子谱增加和toll样受体表达增加一致。慢性NAFLD在WT和APP-Tg小鼠中均诱导AD的晚期病理体征，并且还诱导神经元凋亡。在WT和APP-Tg小鼠中，持续给予HFD后，我们观察到参与β-淀粉样蛋白清除的低密度脂蛋白受体相关蛋白-1（LRP-1）的脑表达降低。LRP-1表达与慢性NAFLD病程中AD的晚期体征相关。在急性NAFLD期间将小鼠从HFD中移除逆转了肝脏病理学，减少了活化的小胶质细胞和神经炎症的迹象，并降低了β-淀粉样蛋白斑块负荷。我们的研究结果表明，在没有遗传易感性的情况下，脑外诱导的慢性炎症足以诱导神经退行性变。本文的在线版本（doi：10.1186/s12974-015-0467-5）包含补充材料，可供授权用户使用。
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and subsequent liver pathology. Obesity and consumption of a high-fat diet are known to increase the risk of Alzheimer’s disease (AD). Here, we investigated NAFLD-induced liver inflammation in the pathogenesis of AD. WT and APP-Tg mice were fed with a standard diet (SD) or a high-fat diet (HFD) for 2, 5 months, or 1 year to induce NAFLD. Another set of APP-Tg mice were removed from HFD after 2 months and put back on SD for 3 months. During acute phase NAFLD, WT and APP-Tg mice developed significant liver inflammation and pathology that coincided with increased numbers of activated microglial cells in the brain, increased inflammatory cytokine profile, and increased expression of toll-like receptors. Chronic NAFLD induced advanced pathological signs of AD in both WT and APP-Tg mice, and also induced neuronal apoptosis. We observed decreased brain expression of low-density lipoprotein receptor-related protein-1 (LRP-1) which is involved in β-amyloid clearance, in both WT and APP-Tg mice after ongoing administration of the HFD. LRP-1 expression correlated with advanced signs of AD over the course of chronic NAFLD. Removal of mice from HFD during acute NAFLD reversed liver pathology, decreased signs of activated microglial cells and neuro-inflammation, and decreased β-amyloid plaque load. Our findings indicate that chronic inflammation induced outside the brain is sufficient to induce neurodegeneration in the absence of genetic predisposition. The online version of this article (doi:10.1186/s12974-015-0467-5) contains supplementary material, which is available to authorized users.