Mass and relative elution time profiling: two-dimensional analysis of sphingolipids in Alzheimer's disease brains

Hejazi, Leila; Wong, Jason; Cheng, Danni; Proschogo, Nicholas; Ebrahimi, Diako; Garner, Brett; Don, Anthony S.

doi:10.1042/bj20110566

Cited by 45 publications

(32 citation statements)

References 40 publications

(33 reference statements)

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“…C12:0 sulfatide and C12:0 galactosylceramide internal standards were added at 250 pmoles/sample. Data processing was carried out using the MMSAT program [26] and the detected sphingomyelin and sulfatide species were verified as conforming to a previously identified quadratic elution profile [27]. Lipids, expressed as ratios to the relevant internal standard, were quantified using standard curves prepared with sphingomyelin, galactosylceramide, and sulfatide external standards (Avanti Polar Lipids).…”

Section: Lipid Assaymentioning

confidence: 99%

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

Don

Hsiao

Bleasel

et al. 2014

Acta Neuropathologica Communications

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Multiple system atrophy (MSA) is a rapidly-progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. A pathological hallmark of MSA is the presence of α-synuclein deposits in oligodendrocytes, the myelin-producing support cells of the brain. Brain pathology and in vitro studies indicate that myelin instability may be an early event in the pathogenesis of MSA. Lipid is a major constituent (78% w/w) of myelin and has been implicated in myelin dysfunction in MSA. However, changes, if any, in lipid level/distribution in MSA brain are unknown. Here, we undertook a comprehensive analysis of MSA myelin. We quantitatively measured three groups of lipids, sphingomyelin, sulfatide and galactosylceramide, which are all important in myelin integrity and function, in affected (under the motor cortex) and unaffected (under the visual cortex) white matter regions. For all three groups of lipids, most of the species were severely decreased (40-69%) in affected but not unaffected MSA white matter. An analysis of the distribution of lipid species showed no significant shift in fatty acid chain length/content with MSA. The decrease in lipid levels was concomitant with increased α-synuclein expression. These data indicate that the absolute levels, and not distribution, of myelin lipids are altered in MSA, and provide evidence for myelin lipid dysfunction in MSA pathology. We propose that dysregulation of myelin lipids in the course of MSA pathogenesis may trigger myelin instability.

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Section: Lipid Assaymentioning

confidence: 99%

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

Don

Hsiao

Bleasel

et al. 2014

Acta Neuropathologica Communications

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“…A highly specific SPHK1 inhibitor, although not affecting GBM cell proliferation, potently inhibits the transfer of angiogenic signals from GBM cells to cocultured endothelial cells. Sphingolipid Quantification by LC-MS/MS-Lipid extraction and sphingolipid quantification was performed as described previously (25,26). Sphingomyelins were analyzed separately following an additional alkaline hydrolysis step as described (26,27).…”

mentioning

confidence: 99%

“…Sphingolipid Quantification by LC-MS/MS-Lipid extraction and sphingolipid quantification was performed as described previously (25,26). Sphingomyelins were analyzed separately following an additional alkaline hydrolysis step as described (26,27). Lipids were quantified relative to external standards for each lipid class as ratios to relevant internal standards: 1250 pmol d18:1/12:0 SM; 250 pmol each of d18:1/12:0 HexCer and d18: 1/12:0 sulfatide; and 50 pmol each of d18:1/17:0 ceramide, d17:1 sphingosine, and d17:1 S1P.…”

mentioning

confidence: 99%

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

Abuhusain¹,

Matin

Qiao

et al. 2013

Journal of Biological Chemistry

135

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Background:The sphingolipid metabolite sphingosine 1-phosphate (S1P) is a potent angiogenic factor. Results: S1P content is 9-fold higher in glioblastomas compared with normal brain, and S1P production is necessary for glioblastoma cells to trigger endothelial cell angiogenesis. Conclusion: Excessive S1P synthesis is a major contributor to glioblastoma angiogenesis. Significance: Inhibiting S1P synthesis may be a valuable antiangiogenic approach in glioblastoma.

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“…Given that ceramide results from sulfatide degradation, these results indicate decreased sulfatide metabolism in the AD brain. Immunohistochemical studies have shown that the ceramide levels are increased mainly in astrocytes [113] , suggesting that neurons may have a lipid metabolism different from that of glial cells. White-matter ceramides are increased 3-fold in the AD temporal cortex and cerebellum during the early stage of the disease [109] .…”

Section: Role Of Fatty-acid Metabolism In Ad Pathogenesismentioning

confidence: 99%

“…However, gray-matter ceramides are unchanged at all stages of AD [109] . Recently, a study showed that hippocampal ceramide levels are decreased [113] . In [110][111][112][113][114] , and ceramide in turn influences Aβ production by stabilizing β-secretase and promoting the amyloidogenic pathway of APP processing [115,116] .…”

Section: Role Of Fatty-acid Metabolism In Ad Pathogenesismentioning

confidence: 99%

Lipid metabolism in Alzheimer’s disease

Liu

Zhang

2014

Neurosci. Bull.

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Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis. Keywords: brain aging; lipid metabolism; Alzheimer's disease ·Review· IntroductionLipids are abundant in the brain. These lipids consist of glycerophospholipids (GPs), sphingolipids, and cholesterol in roughly equimolar proportions [1] . The brain contains about 20% of the total body cholesterol [2] . Cholesterol is primarily derived from local synthesis, whereas uptake of lipoprotein particle-derived cholesterol from the peripheral circulation is usually prevented by the blood-brain-barrier. Lipids, especially cholesterol, have recently been extensively studied in many neurodegenerative diseases. Impairment of cholesterol metabolism (synthesis, transport, and utilization by neurons) in the brain is linked to Alzheimer's disease (AD) and the aging process. In addition, lipid oxidation products accumulate at high levels in aging tissues in mice [3] . Recent studies have demonstrated the important role of altered metabolism in AD [4] . Sphingomyelinases promote apoptosis in human primary neurons through the generation of a proapoptotic molecule, ceramide [5] .Moreover, upregulated arachidonic acid metabolism has been reported in hAPP-J20 AD mice as well as in the AD brain, particularly in regions having high densities of senile plaques with activated microglia [6,7] . Although the potential link between cholesterol and AD pathogenesis has been intensively studied, growing evidence suggests that other lipids, such as sphingolipids and GPs, also play an important role. Here, we review some recent advances in understanding the role lipids play in the aging process and AD pathogenesis. Major Lipid Classes and Functions in the BrainAlthough most lipids serve as structural lipids in cell membranes, they are also directly involved in membrane trafficking, intracellular architecture, and the regulation of proteins and sub-compartments in membranes (lipid rafts) (Table 1). Eukaryotic organisms might contain a dozen major lipid classes, each comprising hundreds of individual molecular species [8] . Lipids have the potential to generate 9 000-100 000 molecular species [9,10] , and a mammalian cell may contain 1 000-2 000 [11] . The brain is one of the most lipid-enriched organs, containing several major classes, such as cholesterol, GPs, sphingolipids and fatty acids [12] . The biological significance of the compositional complexity of lipids is poorly understood. However, the recent development of the shot-gun lipidomics technique may provide more sensitive and quant...

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Mass and relative elution time profiling: two-dimensional analysis of sphingolipids in Alzheimer's disease brains

Cited by 45 publications

References 40 publications

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

Lipid metabolism in Alzheimer’s disease

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