Kim Do-Geun, Krenz Antje, Toussaint Leon E, Maurer Kirk J, Robinson Sudie-Ann, Yan Angela, Torres Luisa, Bynoe Margaret S
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
J Neuroinflammation. 2016 Jan 5;13:1. doi: 10.1186/s12974-015-0467-5.
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.
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。它由高脂饮食引起，其特征是肝脏炎症及随后的肝脏病变。已知肥胖和高脂饮食会增加患阿尔茨海默病（AD）的风险。在此，我们研究了NAFLD诱导的肝脏炎症在AD发病机制中的作用。
将野生型（WT）和淀粉样前体蛋白转基因（APP-Tg）小鼠分别喂食标准饮食（SD）或高脂饮食（HFD）2个月、5个月或1年以诱导NAFLD。另一组APP-Tg小鼠在喂食HFD 2个月后改为喂食SD 3个月。
在急性期NAFLD期间，WT和APP-Tg小鼠出现了明显的肝脏炎症和病变，同时大脑中活化小胶质细胞数量增加、炎症细胞因子水平升高以及Toll样受体表达增加。慢性NAFLD在WT和APP-Tg小鼠中均诱导了AD的晚期病理体征，还诱导了神经元凋亡。在持续给予HFD后，我们观察到WT和APP-Tg小鼠大脑中参与β-淀粉样蛋白清除的低密度脂蛋白受体相关蛋白1（LRP-1）表达降低。在慢性NAFLD过程中，LRP-1表达与AD的晚期体征相关。在急性期NAFLD期间将小鼠从HFD改为SD可逆转肝脏病变，减少活化小胶质细胞和神经炎症的体征，并降低β-淀粉样斑块负荷。
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发神经退行性变。
