Fu YuHong, He Ying, Phan Katherine, Pickford Russell, Kim Young-Bum, Dzamko Nicolas, Halliday Glenda M, Kim Woojin Scott
Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia.
Faculty of Medicine and Health, School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia.
Brain Commun. 2022 May 11;4(3):fcac120. doi: 10.1093/braincomms/fcac120. eCollection 2022.
Alzheimer's disease is a devastating neurodegenerative disease that affects more women than men. The pathomechanism underlying the sex disparity, especially in the brain, is unclear. is one of the strongest susceptibility genes for Alzheimer's disease. It mediates the transport of lipids across membranes and is associated with pathways related to amyloid-β neuropathology. However, the role of ABCA7 in the regulation of brain lipids is largely unknown. Sex-specific differences in the pathological link between brain lipid dysregulation and amyloid-β are also unknown. Here, we undertook quantitative discovery lipidomics of male and female knockout ( = 52) and wild type ( = 35) mouse brain using sophisticated liquid chromatography/mass spectrometry. We identified 61 lipid subclasses in the mouse brain and found sex-specific differences in lipids that were altered with deletion. The altered lipids belong to cellular pathways that control cell signalling, sterol metabolism, mitochondrial function and neuroprotection. We also investigated the relationship between lipids and amyloid-β levels in the knockout mice and found elevated free cholesterol only in female mice that was significantly correlated with amyloid-β42 levels. In male knockout mice, the neuroprotective ganglioside GD1a levels were elevated and inversely correlated with amyloid-β42 levels. Collectively, these results demonstrate that deletion leads to sex-specific lipid dysregulation in the brain, providing insight into the underlying sex disparity in the aetiology of Alzheimer's disease.
阿尔茨海默病是一种毁灭性的神经退行性疾病，女性患者多于男性。这种性别差异背后的病理机制，尤其是在大脑中的机制尚不清楚。 是阿尔茨海默病最强的易感基因之一。它介导脂质跨膜运输，并与淀粉样β神经病理学相关的通路有关。然而，ABCA7在脑脂质调节中的作用在很大程度上尚不清楚。脑脂质失调与淀粉样β之间病理联系的性别特异性差异也不清楚。在这里，我们使用先进的液相色谱/质谱法对雄性和雌性 基因敲除小鼠（ = 52）和野生型小鼠（ = 35）的脑进行了定量发现脂质组学研究。我们在小鼠脑中鉴定出61种脂质亚类，并发现随着 基因缺失而改变的脂质存在性别特异性差异。这些改变的脂质属于控制细胞信号传导、甾醇代谢、线粒体功能和神经保护的细胞通路。我们还研究了基因敲除小鼠中脂质与淀粉样β水平之间的关系，发现仅在雌性小鼠中游离胆固醇升高，且与淀粉样β42水平显著相关。在雄性基因敲除小鼠中，神经保护性神经节苷脂GD1a水平升高，且与淀粉样β42水平呈负相关。总的来说，这些结果表明 基因缺失导致大脑中出现性别特异性脂质失调，为阿尔茨海默病病因学中潜在的性别差异提供了见解。
