Neuronal human BACE1 knockin induces systemic diabetes in mice.
Neuronal human BACE1 knockin induces systemic diabetes in mice.
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DOI：
10.1007/s00125-016-3960-1
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发表时间：
2016-07
期刊：
影响因子：
8.2
通讯作者：
Platt B
中科院分区：
文献类型：
--
作者：
Plucińska K;Dekeryte R;Koss D;Shearer K;Mody N;Whitfield PD;Doherty MK;Mingarelli M;Welch A;Riedel G;Delibegovic M;Platt B
β-分泌酶 1 (BACE1) 是阿尔茨海默病发病机制中的关键酶，可催化淀粉样前体蛋白 (APP) 的淀粉样蛋白生成裂解。最近，Bace1 整体缺失被证明可以预防饮食引起的肥胖和糖尿病，这表明 BACE1 是葡萄糖稳态的潜在调节剂。在这里，我们使用神经元特异性人类 BACE1 敲入小鼠模型 (PLB4) 研究了神经元 BACE1 的增加是否足以改变全身葡萄糖代谢。通过葡萄糖耐量试验和 EchoMRI 测定血糖稳态和肥胖情况，通过定量脂质组学测量脂质种类，通过蛋白质印迹、定量 PCR 和 ELISA 评估生化和分子变化。通过 18FDG-PET 成像测量大脑和上半身的葡萄糖摄取。生理和分子分析表明，集中表达的人 BACE1 从 4 个月大起会诱导小鼠出现全身性葡萄糖不耐受，并伴有脂肪肝表型和肝糖原储存受损。这种糖尿病表型与下丘脑病理学相关，即黑皮质素系统失调，以及中枢 C/EBP 同源蛋白 (CHOP) 信号传导升高及其调节真核翻译起始因子 2α (eIF2α) 过度磷酸化表明的晚期内质网 (ER) 应激。体内 18FDG-PET 成像进一步证实了这些小鼠的脑葡萄糖代谢低下；这与神经元胰岛素相关信号传导的改变、蛋白酪氨酸磷酸酶 1B (PTP1B) 和视黄醇结合蛋白 4 (RBP4) 水平的增强以及核糖体蛋白和脂质翻译机制的上调相对应。通过脂质组学分析发现前脑和血浆脂质积累（即神经酰胺、三酰甘油、磷脂）增加。我们的数据表明，神经元 BACE1 是代谢稳态的关键调节因子，并为阿尔茨海默病中代谢紊乱的高患病率提供了潜在机制。本文的在线版本 (doi:10.1007/s00125-016-3960-1) 包含经过同行评审但未经编辑的补充材料，可供授权用户使用。
β-Secretase 1 (BACE1) is a key enzyme in Alzheimer’s disease pathogenesis that catalyses the amyloidogenic cleavage of amyloid precursor protein (APP). Recently, global Bace1 deletion was shown to protect against diet-induced obesity and diabetes, suggesting that BACE1 is a potential regulator of glucose homeostasis. Here, we investigated whether increased neuronal BACE1 is sufficient to alter systemic glucose metabolism, using a neuron-specific human BACE1 knockin mouse model (PLB4). Glucose homeostasis and adiposity were determined by glucose tolerance tests and EchoMRI, lipid species were measured by quantitative lipidomics, and biochemical and molecular alterations were assessed by western blotting, quantitative PCR and ELISAs. Glucose uptake in the brain and upper body was measured via 18FDG-PET imaging. Physiological and molecular analyses demonstrated that centrally expressed human BACE1 induced systemic glucose intolerance in mice from 4 months of age onward, alongside a fatty liver phenotype and impaired hepatic glycogen storage. This diabetic phenotype was associated with hypothalamic pathology, i.e. deregulation of the melanocortin system, and advanced endoplasmic reticulum (ER) stress indicated by elevated central C/EBP homologous protein (CHOP) signalling and hyperphosphorylation of its regulator eukaryotic translation initiation factor 2α (eIF2α). In vivo 18FDG-PET imaging further confirmed brain glucose hypometabolism in these mice; this corresponded with altered neuronal insulin-related signalling, enhanced protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4) levels, along with upregulation of the ribosomal protein and lipid translation machinery. Increased forebrain and plasma lipid accumulation (i.e. ceramides, triacylglycerols, phospholipids) was identified via lipidomics analysis. Our data reveal that neuronal BACE1 is a key regulator of metabolic homeostasis and provide a potential mechanism for the high prevalence of metabolic disturbance in Alzheimer’s disease. The online version of this article (doi:10.1007/s00125-016-3960-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.