A high-fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the App(NL-F/NL-F) knock-in mouse model.
A high-fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the App(NL-F/NL-F) knock-in mouse model.
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DOI：
10.1111/acel.13429
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发表时间：
2021-08
期刊：
影响因子：
7.8
通讯作者：
Nakabeppu Y
中科院分区：
文献类型：
--
作者：
Mazzei G;Ikegami R;Abolhassani N;Haruyama N;Sakumi K;Saito T;Saido TC;Nakabeppu Y
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，但也存在一些争议。为了克服来自转基因的潜在伪产物，我们使用敲入小鼠模型AppNL - F/NL - F，该模型从6个月大开始积累a β斑块，并在18个月大时表现出轻度认知障碍，没有过量产生APP。在本研究中，6个月大的雄性AppNL - 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治疗导致野生型和AppNL−F/NL−F小鼠肥胖和糖耐量受损（即T2DM），但只有后者表现出认知功能受损，并伴有海马中Aβ沉积和小胶质增生的显著增加以及胰岛素抵抗。此外，HFD喂养的AppNL−F/NL−F小鼠齿状回颗粒细胞层的体积显著减少，颗粒细胞细胞核中8 -氧鸟嘌呤（一种氧化的鸟嘌呤碱）的积累增加。微阵列基因表达谱显示，无论饮食如何，两种小鼠海马细胞类型的数量没有显著差异。此外，HFD处理降低了AppNL−F/NL−F小鼠中Aβ结合蛋白转甲状腺素（TTR）的表达，表明TTR的消耗是HFD喂养的AppNL−F/NL−F小鼠海马中Aβ沉积增加的原因。胰岛素抵抗和糖尿病是阿尔茨海默病（AD）的主要危险因素。在本文中，我们在敲入AD小鼠模型App NL - F/NL - F中发现，慢性高脂饮食治疗诱导的2型糖尿病加重了先前存在的AD病理，如a β沉积、小胶质细胞增生和氧化性DNA损伤。这伴随着转甲状腺素的表达减少，转甲状腺素是一种可以与a β肽结合，抑制其聚集并促进其清除的蛋白质。
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, AppNL−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 AppNL−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 AppNL−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 AppNL−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 AppNL−F/NL−F mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD‐fed AppNL−F/NL−F mice. Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD). In this paper, we showed that type 2 diabetic conditions induced by chronic high‐fat diet treatment exacerbated pre‐existing AD pathology such as Aβ deposition, microgliosis, and oxidative DNA damage in a knock‐in mouse model of AD, App NL‐F/NL‐F. This was accompanied by decreased expression of transthyretin, a protein that can bind to the Aβ peptide, suppress its aggregation, and promote its clearance.
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影响因子：
3.7
作者：
Barron AM;Rosario ER;Elteriefi R;Pike CJ
通讯作者：
Pike CJ
影响因子：
7.8
作者：
Elhaik Goldman S;Goez D;Last D;Naor S;Liraz Zaltsman S;Sharvit-Ginon I;Atrakchi-Baranes D;Shemesh C;Twitto-Greenberg R;Tsach S;Lotan R;Leikin-Frenkel A;Shish A;Mardor Y;Schnaider Beeri M;Cooper I
通讯作者：
Cooper I
影响因子：
5.3
作者：
Choi, Se Hoon;Leight, Susan N.;Sisodia, Sangram S.
通讯作者：
Sisodia, Sangram S.
DOI：
10.1073/pnas.0712197105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Buxbaum, Joel N.;Ye, Zhengyi;Bartfai, Tamas
通讯作者：
Bartfai, Tamas
影响因子：
5.6
作者：
de la Monte, Suzanne M.
通讯作者：
de la Monte, Suzanne M.