BACKGROUND Metabolic syndrome, the development of which is associated with high-caloric Western diet (HCD) intake, represent a risk factor for mild cognitive impairment (MCI) and dementia including Alzheimer's disease (AD) later in life. This study aimed to investigate the effect of diet-induced metabolic disturbances on white matter neuroinflammation and cognitive function in a transgenic (TG) Fischer 344 rat carrying a human β-amyloid precursor protein (APP) gene with Swedish and Indiana mutations (APP21 TG), a model of pre-AD and MCI. METHODS TG and wildtype (WT) rats received either a HCD with 40% kJ from fat supplemented with 20% corn syrup drink or a standard diet for 12 weeks. Body weight, caloric intake, and blood pressure were measured repeatedly. End-point changes in glucose and lipid metabolism were also assessed. Open field task was used for assessment of activity; Morris water maze was used to assess spatial learning and memory. Cerebral white matter microglia and astrocytes, hippocampal neurons, and neuronal synapses were examined using immunohistochemistry. RESULTS Rats maintained on the HCD developed significant obesity, visceral adiposity, dyslipidemia, and hyperinsulinemia, but did not become hypertensive. Impaired glucose tolerance was observed only in WT rats on the HCD. Total microglia number, activated OX-6+ microglia, as well as GFAP+ astrocytes located predominantly in the white matter were greater in the APP21 TG rat model in comparison to WT rats. HCD-driven metabolic perturbations further exacerbated white matter microgliosis and microglia cell activation in the APP21 TG rats and led to detectable changes in spatial reference memory in the comorbid prodromal AD and metabolic syndrome group compared to WT control rats. Neuronal density in the CA1 subregion of the hippocampus was not different between the experimental groups. Synaptic density in the CA1 and CA3 hippocampal subregions was lower in the TG rats compared to WT rats; however, there was no additional effect of the co-morbidity on this measure. CONCLUSIONS These results suggest that white matter neuroinflammation might be one of the possible processes of early interaction of metabolic syndrome with MCI and pre-AD and could be one of the early brain pathologies contributing to cognitive deficits observed in mild cognitive impairment and dementia, including AD cases.

中文翻译：

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共病代谢综合征和前驱性阿尔茨海默氏病大鼠模型中的白质炎症和认知功能。

背景技术代谢综合症的发展与高热量的西方饮食（HCD）的摄入有关，是生命后期出现轻度认知障碍（MCI）和痴呆症（包括阿尔茨海默氏病（AD））的危险因素。这项研究旨在调查饮食引起的代谢紊乱对转基因（TG）Fischer 344大鼠的白质神经炎症和认知功能的影响，该大鼠携带带有瑞典和印第安纳州突变（APP21 TG）的人β-淀粉样蛋白（APP）基因，是AD之前和MCI的模型。方法TG和野生型（WT）大鼠以脂肪补充40％kJ的HCD或20％玉米糖浆饮料或标准饮食喂养12周。重复测量体重，热量摄入和血压。还评估了葡萄糖和脂质代谢的终点变化。野外任务用于评估活动；莫里斯水迷宫被用来评估空间学习和记忆。使用免疫组织化学检查了脑白质小胶质细胞和星形胶质细胞，海马神经元和神经元突触。结果维持HCD的大鼠出现了严重的肥胖，内脏脂肪异常，血脂异常和高胰岛素血症，但并未出现高血压。仅在HCD上的WT大鼠中观察到葡萄糖耐量受损。与WT大鼠相比，APP21 TG大鼠模型的总小胶质细胞数量，活化的OX-6 +小胶质细胞以及主要位于白质中的GFAP +星形胶质细胞更大。与WT对照大鼠相比，HCD驱动的代谢扰动进一步加剧了APP21 TG大鼠中的白质小胶质细胞增生和小胶质细胞活化，并导致合并症的前驱AD和代谢综合征组的空间参考记忆发生可检测的变化。实验组之间，海马CA1区的神经元密度没有差异。TG大鼠的CA1和CA3海马区的突触密度低于WT大鼠。但是，并存病对此措施没有其他影响。