Diet-induced insulin resistance elevates hippocampal glutamate as well as VGLUT1 and GFAP expression in AβPP/PS1 mice
Diet-induced insulin resistance elevates hippocampal glutamate as well as VGLUT1 and GFAP expression in AβPP/PS1 mice
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DOI：
10.1111/jnc.14634
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发表时间：
2019-01-01
影响因子：
4.7
通讯作者：
Hascup, Kevin N.
中科院分区：
文献类型：
--
作者：
Hascup, Erin R.;Broderick, Sarah O.;Hascup, Kevin N.
阿尔茨海默病（AD）的发病机制发展了几十年，表明可改变的生活方式因素可能有助于疾病的发病机制。在人类中，与2型糖尿病相关的高胰岛素血症增加了发生AD的风险，并且这两种疾病具有相似的年龄相关病因，包括淀粉样蛋白生成。由于我们已经证明可溶性A β（42）促进谷氨酸释放，我们想了解饮食诱导的胰岛素抵抗如何改变海马谷氨酸动力学，这对记忆的形成和巩固很重要。将8至12周龄的C57 BL/6 J和A β PP/PS1小鼠置于低脂饮食或高脂饮食（HFD）中8个月。HFD导致C57 BL/6 J和A β PP/PS1小鼠的体重显著增加以及胰岛素敏感性、葡萄糖耐量和学习能力受损。β PP/PS1低脂饮食小鼠的海马基底以及刺激诱发的谷氨酸释放升高，随着HFD的消耗进一步增加。免疫组化结果表明，与细胞外谷氨酸升高相对应的海马亚区囊泡谷氨酸转运蛋白1和胶质细胞酸性蛋白密度增加。虽然没有观察到海马斑块负荷的差异，但A β PP/PS1 HFD小鼠中斑块周围的星形胶质细胞反应升高可能是控制斑块积聚的补偿机制。这些数据支持A β PP/PS1小鼠具有慢性升高的细胞外谷氨酸，其由HFD加重，并且可改变的生活方式因素如肥胖诱导的胰岛素抵抗可促成AD发病机制。这篇文章获得了 *Open Materials* 和 *Open Data* 的徽章，因为它使数据公开可用。这些数据可在（数据的数字）和（材料和方法）查阅。本文的完整开放科学披露表格可以在文章末尾找到。有关开放实践徽章的更多信息，请访问。本期封面图片：doi：.
The symptomologies of Alzheimer's disease (AD) develop over decades suggesting modifiable lifestyle factors may contribute to disease pathogenesis. In humans, hyperinsulinemia associated with type 2 diabetes mellitus increases the risk for developing AD and both diseases share similar age-related etiologies including amyloidogenesis. Since we have demonstrated that soluble A beta(42) elicits glutamate release, we wanted to understand how diet-induced insulin resistance alters hippocampal glutamate dynamics, which are important for memory formation and consolidation. Eight to twelve-week-old C57BL/6J and A beta PP/PS1 mice were placed on either a low-fat diet or high-fat diet (HFD) for 8 months. A HFD led to significant weight increases as well as impaired insulin sensitivity, glucose tolerance, and learning in both C57BL/6J and A beta PP/PS1 mice. A beta PP/PS1 low-fat diet mice had elevated hippocampal basal as well as stimulus-evoked glutamate release that was further increased with consumption of a HFD. Immunohistochemistry indicated an increase in vesicular glutamate transporter 1 and glial fibrillary acidic protein density in hippocampal subregions corresponding with this elevated extracellular glutamate. While no differences in hippocampal plaque load were observed, the elevated astrogliotic response surrounding the plaques in A beta PP/PS1 HFD mice may have been a compensatory mechanism to control plaque accumulation. These data support that A beta PP/PS1 mice have chronically elevated extracellular glutamate that is exacerbated by a HFD and that modifiable lifestyle factors such as obesity-induced insulin resistance can contribute to AD pathogenesis. Open science badges This article has received a badge for *Open Materials* and for *Open Data* because it made the data publicly available. The data can be accessed at (figures for data) and (materials and methods). The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at . Cover Image for this issue: doi: .