Lipid dysregulation is associated with several key characteristics of Alzheimer’s disease (AD), including amyloid-β and tau neuropathology, neurodegeneration, glucose hypometabolism, as well as synaptic and mitochondrial dysfunction. The β-site amyloid precursor protein cleavage enzyme 1 (BACE1) is associated with increased amyloidogenesis, and has been affiliated with diabetes via its role in metabolic regulation. The research presented herein investigates the role of hBACE1 in lipid metabolism and whether specific brain regions show increased vulnerability to lipid dysregulation. By utilising advanced mass spectrometry techniques, a comprehensive, quantitative lipidomics analysis was performed to investigate the phospholipid, sterol, and fatty acid profiles of the brain from the well-known PLB4 hBACE1 knock-in mouse model of AD, which also shows a diabetic phenotype, to provide insight into regional alterations in lipid metabolism. Results show extensive region – specific lipid alterations in the PLB4 brain compared to the wild-type, with decreases in the phosphatidylethanolamine content of the cortex and triacylglycerol content of the hippocampus and hypothalamus, but increases in the phosphatidylcholine, phosphatidylinositol, and diacylglycerol content of the hippocampus. Several sterol and fatty acids were also specifically decreased in the PLB4 hippocampus. Collectively, the lipid alterations observed in the PLB4 hBACE1 knock-in AD mouse model highlights the regional vulnerability of the brain, in particular the hippocampus and hypothalamus, to lipid dysregulation, hence supports the premise that metabolic abnormalities have a central role in both AD and diabetes.

中文翻译：

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阿尔茨海默氏病PLB4 hBACE1敲入小鼠模型中的脑区域特异性脂质改变。

脂质失调与阿尔茨海默氏病（AD）的几个关键特征有关，包括淀粉样β和tau神经病理学，神经退行性疾病，葡萄糖代谢异常以及突触和线粒体功能障碍。β-位淀粉样蛋白前体蛋白裂解酶1（BACE1）与淀粉样蛋白生成增加有关，并通过其在代谢调节中的作用与糖尿病有关。本文介绍的研究调查了hBACE1在脂质代谢中的作用，以及特定的大脑区域是否显示出对脂质失调的增加的脆弱性。利用先进的质谱技术，进行了全面的定量脂质组学分析，以研究AD的PLB4 hBACE1敲入小鼠模型的大脑的磷脂，固醇和脂肪酸谱，它也显示出糖尿病的表型，以提供对脂质代谢区域变化的见解。结果显示，与野生型相比，PLB4脑中存在特定区域的脂质变化，皮层的磷脂酰乙醇胺含量降低，海马和下丘脑的三酰基甘油含量降低，但磷脂酰胆碱，磷脂酰肌醇和二酰基甘油含量增加海马。在PLB4海马中，几种固醇和脂肪酸也被特异性降低。总的来说，在PLB4 hBACE1敲入AD小鼠模型中观察到的脂质改变突出显示了大脑（特别是海马和下丘脑）对脂质失调的区域脆弱性，因此支持了代谢异常在AD和AD中都起着核心作用的前提。糖尿病。