Chen Y L, Wang L M, Chen Y, Gao J Y, Marshall C, Cai Z Y, Hu G, Xiao M
Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029, China.
Department of Rehabilitation Sciences, University of Kentucky Center of Excellence in Rural Health, Hazard, KY, USA.
Neuroscience. 2016 Mar 1;316:178-91. doi: 10.1016/j.neuroscience.2015.12.039. Epub 2015 Dec 24.
Cholesterol is an essential substance for maintaining normal structure and function of the brain. But unfortunately, a long-term high-cholesterol diet can lead to a variety of pathological changes of the brain such as β-amyloid (Aβ) accumulation, Tau hyperphosphorylation, reactive gliosis, neuroinflammation, neuronal death and synaptic degeneration. These pathological changes have complex internal relations with one other, causing memory impairment and participating in the pathogenesis of Alzheimer's disease (AD). However, early hypercholesterolemia-induced events that lead to brain deterioration are not clear. To address this, 6-month-old female mice were fed a 3% cholesterol diet for 8weeks, followed by behavioral, biochemical and neuropathological analyses. The high-cholesterol-fed mice did not show neuronal and synaptic impairment or cognitive deficits compared with mice given a normal diet, but astrocytes were mildly activated with increased expression of functional markers including apolipoprotein E and aquaporin 4 in the hippocampus. Hippocampal interleukin-1β expression slightly increased, but interleukin-6 (IL-6) and tumor necrosis factor-α did not change significantly compared with those in the control group. Levels of Aβ, and its precursor protein, were unaffected, but levels of presenilin 1 and insulin-degrading enzyme (IDE), that initiate Aβ generation and degradation, respectively, increased in the hippocampus of the model mice. In addition, Tau phosphorylation levels were not different between the control and model groups. These results suggest that changes in astrocyte functional markers and Aβ metabolism proteins, which contribute to maintaining brain cholesterol and Aβ homeostasis, are early events in the process of hypercholesterolemia-related neuropathological changes.
胆固醇是维持大脑正常结构和功能所必需的物质。但不幸的是，长期高胆固醇饮食会导致大脑发生多种病理变化，如β-淀粉样蛋白（Aβ）积累、Tau蛋白过度磷酸化、反应性胶质细胞增生、神经炎症、神经元死亡和突触退化。这些病理变化相互之间存在复杂的内在联系，会导致记忆障碍并参与阿尔茨海默病（AD）的发病机制。然而，早期高胆固醇血症引发的导致脑功能恶化的事件尚不清楚。为了解决这个问题，给6个月大的雌性小鼠喂食3%胆固醇饮食8周，随后进行行为、生化和神经病理学分析。与喂食正常饮食的小鼠相比，喂食高胆固醇饮食的小鼠未表现出神经元和突触损伤或认知缺陷，但星形胶质细胞轻度激活，海马中包括载脂蛋白E和水通道蛋白4在内的功能标志物表达增加。海马白细胞介素-1β表达略有增加，但与对照组相比，白细胞介素-6（IL-6）和肿瘤坏死因子-α没有显著变化。Aβ及其前体蛋白的水平未受影响，但分别启动Aβ生成和降解的早老素1和胰岛素降解酶（IDE）在模型小鼠海马中的水平升高。此外，对照组和模型组之间的Tau磷酸化水平没有差异。这些结果表明，星形胶质细胞功能标志物和Aβ代谢蛋白的变化有助于维持脑胆固醇和Aβ稳态，是高胆固醇血症相关神经病理变化过程中的早期事件。
