Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer's disease

Fonteh, Alfred N.; Chiang, Jiarong; Cipolla, Matthew; Hale, Jack K.; F, Diallo; Chirino, Alejandra; Arakaki, Xianghong; Harrington, Michael G.

doi:10.1194/jlr.m037622

Cited by 81 publications

(84 citation statements)

References 53 publications

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“…A total lipid extract from 100 mg brain, which is an extremely lipid‐rich tissue, would have to be diluted in a volume of 10 mL or more for routine lipidomic analysis. While other analytical methods applied to NAPE skip extensive sample preparation methods 6, 7, 30, 32, 34, the presented sample cleanup by SPE eliminates many highly abundant lipid classes such as triacylglycerols that consequently enables reconstitution of the NAPE‐containing fraction in a much smaller volume (200 μL). Preliminary testing during method development showed no analyte losses caused by SPE sample preparation.…”

Section: Resultsmentioning

confidence: 99%

Quantitative analysis of N‐acylphosphatidylethanolamine molecular species in rat brain using solid‐phase extraction combined with reversed‐phase chromatography and tandem mass spectrometry

Triebl

Weissengruber

Trötzmüller

et al. 2016

J of Separation Science

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A novel method for the sensitive and selective identification and quantification of N‐acylphosphatidylethanolamine molecular species was developed. Samples were prepared using a combination of liquid–liquid and solid‐phase extraction, and intact N‐acylphosphatidylethanolamine species were determined by reversed‐phase high‐performance liquid chromatography coupled to positive electrospray tandem mass spectrometry. As a result of their biological functions as precursors for N‐acylethanolamines and as signaling molecules, tissue concentrations of N‐acylphosphatidylethanolamines are very low, and their analysis is additionally hindered by the vast excess of other sample components. Our sample preparation methods are able to selectively separate the analytes of interest from any expected biological interferences. Finally, the highest selectivity is achieved by coupling chromatographic separation and two N‐acyl chain specific selected reaction monitoring scans per analyte, enabling identification of both the N‐acyl chain and the phosphatidylethanolamine moiety. The validated method is suitable for the reliable quantification of N‐acylphosphatidylethanolamine species from rat brain with a lower limit of quantification of 10 pmol/g and a linear range up to 2300 pmol/g. In total, 41 N‐acylphosphatidylethanolamine molecular species with six different N‐acyl chains, amounting to a total concentration of 3 nmol/g, were quantified.

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Section: Resultsmentioning

confidence: 99%

Quantitative analysis of N‐acylphosphatidylethanolamine molecular species in rat brain using solid‐phase extraction combined with reversed‐phase chromatography and tandem mass spectrometry

Triebl

Weissengruber

Trötzmüller

et al. 2016

J of Separation Science

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“…CSF phospholipase A 2 activity was measured using a fluorescent assay with a substrate cocktail, as described previously 17. Sphingomyelinase activity was measured using a fluorescent assay kit following the instructions of the manufacturer (Molecular Probes).…”

Section: Methodsmentioning

confidence: 99%

“…SM promoted cholesterol efflux in control, familial high‐density lipoprotein deficiency, or Tangier disease fibroblasts that lack ABCA1 receptors 16. We recently reported alterations in CSF phospholipids and sphingolipids in both the supernatant and brain‐derived nanoparticles from CSF of participants with late‐onset AD 17, 18. The functional relevance of these compartmentalized alterations in CSF phospholipids on cholesterol efflux capacity is not known.…”

Section: Introductionmentioning

confidence: 99%

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

Yassine

Feng

Chiang

et al. 2016

JAHA

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BackgroundAnimal and human studies indicate that ABCA1‐mediated cholesterol transport is important in Alzheimer's disease (AD). We hypothesized that the efficiency of cerebrospinal fluid (CSF) to facilitate ABCA1‐mediated cholesterol efflux would be reduced in participants with mild cognitive impairment (MCI) or AD compared with cognitively healthy participants.Methods and ResultsCSF was collected from a cross‐sectional study of cognitively healthy participants (n=47) and participants with MCI (n=35) or probable AD (n=26).The capacity of CSF to mediate cholesterol transport was assessed using a BHK cell line that can be induced to express the ABCA1 transporter. ABCA1‐mediated cholesterol efflux capacity was 30% less in participants with MCI or AD compared with cognitively healthy participants (P<0.001 for both). Cholesterol efflux capacity correlated with CSF cholesterol content (r=0.37, P<0.001). CSF phosphatidylcholine decreased in participants with MCI and AD compared with cognitively healthy participants (9% less in MCI and 27% less in AD compared with cognitively healthy participants, P=0.01) and correlated with CSF efflux capacity (r=0.3, P=0.001). CSF sphingomyelin also correlated with the efflux capacity (r=0.24, P=0.02). Concentrations of CSF apoA‐I and apoE did not significantly correlate with measures of efflux capacity.ConclusionsIn people with MCI and AD, the capacity of CSF to facilitate ABCA1‐mediated cholesterol efflux is impaired. This lesser cholesterol efflux in MCI supports a pathophysiological role for ABCA1‐mediated cholesterol transport in early neurodegeneration.

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“…The only study of fatty acid levels in CSF was recently reported in Alzheimer's patients (Fonteh et al 2014). An increase in the PLA2 activity has liberated DHA from the breakdown of the neuronal lipid membrane and was related to the abnormal oxidative metabolism (Fonteh et al 2013). The Alzheimer disorder is a neurodegenerative disorder thus radically different in terms of pathogenesis and genetic background.…”

Section: Discussionmentioning

confidence: 99%

Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under l-DOPA, 5-HTP and BH4 Trials

et al. 2015

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Objective/context: We describe the second patient presenting the combination of two homoallelic homozygous nonsense mutations in two genes distant from 1.8 Mb in the chromosome 2p13-3, the methylmalonyl-CoA epimerase gene (MCEE) and the sepiapterin reductase gene (SPR).Case report: The patient was born from consanguineous parents. He has presented a moderate but constant methylmalonic acid (MMA) excretion in urine associated with a mental retardation. The first homozygous mutation was identified in the MCEE gene (c.139C>T; p.Arg47*). Progressive dystonia and cataplexy narcolepsy led to diagnose the second homozygous mutation in the SPR gene: c.751A>T; p.Lys251*. Sepiapterin reductase deficiency (SRD) was characterized by a defect in tetrahydrobiopterin (BH4), the cofactor of several hydroxylases needed for the synthesis of neurotransmitters. A treatment with L-DOPA/carbidopa and 5-HTP dramatically improved the dystonic posture, the mood and the hypersomnia, proving that the pathogenesis was due to SRD. A supplementation with BH4 did not induce additional clinical benefit, although HVA and HIAA increased in CSF. The polyunsaturated fatty acids were measured in CSF as the markers of the neuronal stress. We have shown that DHA and its precursor EPA were high before and during the time course of the different treatments.In conclusion: The patient has inherited two copies of the two mutations from his consanguineous parents in the MCEE and SPR genes in the chromosome 2p13-3. DHA and EPA increased in CSF as a response to the neuronal stress induced by the defect in neurotransmitters or the altered metabolism of the odd-chain fatty acids and cholesterol.

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Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer's disease

Cited by 81 publications

References 53 publications

Quantitative analysis of N‐acylphosphatidylethanolamine molecular species in rat brain using solid‐phase extraction combined with reversed‐phase chromatography and tandem mass spectrometry

Quantitative analysis of N‐acylphosphatidylethanolamine molecular species in rat brain using solid‐phase extraction combined with reversed‐phase chromatography and tandem mass spectrometry

ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under l-DOPA, 5-HTP and BH4 Trials

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