Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock-in mouse model, App^{NL−F/NL−F}, which accumulates Aβ plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6-month-old male App^{NL−F/NL−F} and wild-type mice were fed a regular or high-fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild-type and App^{NL−F/NL−F} mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aβ deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD-fed App^{NL−F/NL−F} mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8-oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aβ binding protein transthyretin (TTR) in App^{NL−F/NL−F} mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD-fed App^{NL−F/NL−F} mice.

中文翻译：

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高脂肪饮食加剧了 AppNL-F/NL-F 敲入小鼠模型海马中的阿尔茨海默病病理

胰岛素抵抗和糖尿病是阿尔茨海默病 (AD) 的主要危险因素，对 AD 转基因小鼠模型的研究提供了支持性证据，但存在一些争议。为了克服来自转基因的潜在伪影，我们使用了敲入小鼠模型App ^NL-F/NL-F，该模型从 6 个月大开始积累 Aβ 斑块，并在 18 个月大时显示出轻度认知障碍，而没有过量产生应用程序。在本研究中，6 个月大的雄性App ^NL-F/NL-F和野生型小鼠被喂食常规或高脂肪饮食 (HFD) 12 个月。HFD 治疗在野生型和App ^NL-F/NL-F中导致肥胖和葡萄糖耐量受损（即 T2DM 病症）小鼠，但只有后一种动物表现出认知功能受损，伴随着海马中 Aβ 沉积和小胶质细胞增生以及胰岛素抵抗的显着增加。此外，喂食 HFD 的App ^NL-F/NL-F小鼠的齿状回颗粒细胞层体积显着减少，颗粒细胞核中 8-氧鸟嘌呤（一种氧化的鸟嘌呤碱基）的积累增加。通过微阵列进行的基因表达谱分析显示，无论饮食如何，两种小鼠系的海马中细胞类型的数量都没有显着差异。此外，HFD 处理降低了App ^{NL-F/NL-F中 Aβ 结合蛋白转甲状腺素蛋白 (TTR) 的表达}小鼠，表明 TTR 的消耗是 HFD 喂养的App ^NL-F/NL-F小鼠海马中 Aβ 沉积增加的基础。