High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation.
High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation.
复制标题
高脂肪饮食通过促进β地点App裂解酶1/衔接蛋白2/网格蛋白复合物的形成来增强淀粉样蛋白前体蛋白（APP）的β地点切割。
DOI：
10.1371/journal.pone.0131199
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kinoshita A
中科院分区：
文献类型：
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作者：
Maesako M;Uemura M;Tashiro Y;Sasaki K;Watanabe K;Noda Y;Ueda K;Asada-Utsugi M;Kubota M;Okawa K;Ihara M;Shimohama S;Uemura K;Kinoshita A
肥胖和 2 型糖尿病是阿尔茨海默病 (AD) 的危险因素。我们报道，高脂肪饮食（HFD）可促进β位点APP裂解酶1（BACE1）对淀粉样前体蛋白（APP）的裂解，但不会增加APP转基因小鼠中BACE1的水平。然而，详细机制仍不清楚。在这里，我们证明 HFD 通过增加 APP 转基因小鼠中的 AP-2 水平来促进 BACE1/适配器蛋白 2 (AP-2)/网格蛋白复合物的形成。在瑞典 APP 过表达的中国仓鼠卵巢 (CHO) 细胞以及 SH-SY5Y 细胞中，AP-2 的过表达促进了 BACE1/AP-2/网格蛋白复合物的形成，从而增加了可溶性 APP β (sAPPβ) 的水平。另一方面，抑制这种三聚体复合物形成的突变体 D495R BACE1 会降低 sAPPβ 的水平。 AP-2的过度表达促进BACE1从细胞表面内化，从而降低细胞表面BACE1水平。因此，我们得出结论，HFD 可能诱导 BACE1/AP-2/网格蛋白复合物的形成，随后将 BACE1 从细胞表面转运到细胞内。这些事件可能与 APP 转基因小鼠中 APP β 位点裂解的增强有关。在这里，我们提供的证据表明，HFD 通过调节 BACE1 的亚细胞运输，促进 APP 裂解。
Obesity and type 2 diabetes are risk factors of Alzheimer’s disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by β-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP-2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH-SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP-2/clathrin complex, increasing the level of the soluble form of APP β (sAPPβ). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPPβ. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of β-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage.