Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/29148

TitleComparative lipidomic analysis of mouse and human brain with Alzheimer disease
Author(s)Chan, Robin B.
Oliveira, Tiago Gil
Cortes, Etty P.
Honig, Lawrence S.
Duff, Karen E.
Small, Scott A.
Wenk, Markus R.
Shui, Guanghou
Di Paolo, Gilbert
Issue date2012
PublisherAmerican Society for Biochemistry and Molecular Biology
JournalThe Journal of Biological Chemistry
Abstract(s)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.
TypeArticle
URIhttp://hdl.handle.net/1822/29148
DOI10.1074/jbc.M111.274142
ISSN0021-9258
Publisher versionhttp://www.jbc.org/cgi/pmidlookup?view=long&pmid=22134919
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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