Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

被引:429
作者
Chan, Robin B. [1 ,3 ]
Oliveira, Tiago G. [1 ,3 ,4 ,5 ]
Cortes, Etty P. [3 ]
Honig, Lawrence S. [2 ,3 ]
Duff, Karen E. [1 ,3 ]
Small, Scott A. [2 ,3 ]
Wenk, Markus R. [6 ,7 ]
Shui, Guanghou [6 ,7 ]
Di Paolo, Gilbert [1 ,3 ]
机构
[1] Columbia Univ, Med Ctr, Dept Pathol & Cell Biol, New York, NY 10032 USA
[2] Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA
[3] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA
[4] Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal
[5] Univ Minho, Life & Hlth Sci Res Inst 3Bs, Portuguese Govt Associate Lab, P-4710057 Braga, Portugal
[6] Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore
[7] Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore
基金
美国国家卫生研究院; 新加坡国家研究基金会;
关键词
AMYLOID-BETA-PEPTIDE; COGNITIVE DEFICITS; COMMON VARIANTS; TRANSGENIC MICE; CHOLESTEROL; METABOLISM; CERAMIDE; PRESENILIN-1; PATHOGENESIS; PATHWAYS;
D O I
10.1074/jbc.M111.274142
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2678 / 2688
页数:11
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