Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease
Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease
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DOI：
10.1074/jbc.m111.274142
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发表时间：
2012-01-20
影响因子：
4.8
通讯作者：
Di Paolo, Gilbert
中科院分区：
文献类型：
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作者：
Chan, Robin B.;Oliveira, Tiago G.;Di Paolo, Gilbert
脂质是脑功能的关键调节剂，并且越来越多地与包括阿尔茨海默病（AD）在内的神经退行性疾病有关。在这里，采用基于系统的方法来确定受AD影响的脑组织的脂质组。具体来说，我们使用液相色谱-质谱分析提取物的前额叶皮层，内嗅皮层，小脑的晚发性AD（LOAD）患者，以及前脑的三个转基因家族性AD（FAD）小鼠模型。虽然小脑缺乏脂质组成的重大改变，我们发现了一个升高的信号池甘油二酯以及鞘脂在AD患者的前额叶皮层。此外，患病的内嗅皮质表现出特异性富集的lysobisphosphatidic酸，鞘磷脂，神经节苷脂GM 3，和胆固醇酯，所有这些都表明共同的致病机制与内溶酶体储存疾病。重要的是，在转基因FAD模型中重现了胆固醇酯和GM 3的显著增加，表明这些小鼠是研究与AD相关的内溶酶体功能障碍的异常脂质代谢的相关工具。最后，磷脂酶D-2的基因消融，挽救了FAD小鼠模型的突触和行为缺陷，使GM 3水平完全正常化。因此，这些数据揭示了磷脂酶D-2的产物磷脂酸和神经节苷脂代谢之间的相互作用，并指出神经节苷脂异常在AD发病机制中的核心作用。总的来说，我们的研究突出了脂质组学的假设产生潜力，并确定了新的区域特异性脂质异常可能与AD发病机制。
Lipids are key regulators of brain function and have been increasingly implicated in neurodegenerative disorders including Alzheimer disease (AD). Here, a systems-based approach was employed to determine the lipidome of brain tissues affected by AD. Specifically, we used liquid chromatography-mass spectrometry to profile extracts from the prefrontal cortex, entorhinal cortex, and cerebellum of late-onset AD(LOAD) patients, as well as the forebrain of three transgenic familial AD (FAD) mouse models. Although the cerebellum lacked major alterations in lipid composition, we found an elevation of a signaling pool of diacylglycerol as well as sphingolipids in the prefrontal cortex of AD patients. Furthermore, the diseased entorhinal cortex showed specific enrichment of lysobisphosphatidic acid, sphingomyelin, the ganglioside GM3, and cholesterol esters, all of which suggest common pathogenic mechanisms associated with endolysosomal storage disorders. Importantly, a significant increase in cholesterol esters and GM3 was recapitulated in the transgenic FAD models, suggesting that these mice are relevant tools to study aberrant lipid metabolism of endolysosomal dysfunction associated with AD. Finally, genetic ablation of phospholipase D-2, which rescues the synaptic and behavioral deficits of an FAD mouse model, fully normalizes GM3 levels. These data thus unmask a cross-talk between the metabolism of phosphatidic acid, the product of phospholipase D-2, and gangliosides, and point to a central role of ganglioside anomalies in AD pathogenesis. Overall, our study highlights the hypothesis generating potential of lipidomics and identifies novel region-specific lipid anomalies potentially linked to AD pathogenesis.