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Sphingolipid metabolism correlates with cerebrospinal fluid Beta amyloid levels in Alzheimer's disease.

Fonteh AN, Ormseth C, Chiang J, Cipolla M, Arakaki X, Harrington MG - PLoS ONE (2015)

Bottom Line: In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction.The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants.In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.

ABSTRACT
Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

No MeSH data available.


Related in: MedlinePlus

Sphingolipid levels are altered in Alzheimer’s disease.Levels of SPs in SF or NP were determined using LC-MS/MS. Fig 3A, 3B, 3C, and 3D are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in SF for CN, MCI or AD subjects. Fig. 3E, 3F, 3G, and 3H are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in NP for CN, MCI or AD subjects. Group comparisons were performed using Kruskal Wallis test and non-parametric comparisons using Mann Whitney test and differences between cognitive groups indicated when P < 0.05.
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pone.0125597.g003: Sphingolipid levels are altered in Alzheimer’s disease.Levels of SPs in SF or NP were determined using LC-MS/MS. Fig 3A, 3B, 3C, and 3D are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in SF for CN, MCI or AD subjects. Fig. 3E, 3F, 3G, and 3H are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in NP for CN, MCI or AD subjects. Group comparisons were performed using Kruskal Wallis test and non-parametric comparisons using Mann Whitney test and differences between cognitive groups indicated when P < 0.05.

Mentions: We next quantified the abundance of SP classes in SF from CN, MCI and AD. Although mean SM levels in all three clinical groups were similar, we noticed a slight decrease in MCI and AD (Fig 3A). Levels of Cer and dhCer were not different when comparing CN to MCI (Fig 3B and 3C). In contrast, there was an increase in Cer and dhCer in AD (Fig 3B and 3C). The slight decrease in SM (-7.3% for AD) concomitant with the increase in Cer (21.8% for AD) in CSF was more evident when we compared the ratio SM/Cer in CN to that of AD (Fig 3D). A similar study examining SP changes in NP fractions revealed a decrease in the mean levels of SM (Fig 3E), Cer (Fig 3F, P < 0.05) and dhCer (Fig 3G) in AD compared with CN such that the ratio SM/Cer did not change (Fig 3H).


Sphingolipid metabolism correlates with cerebrospinal fluid Beta amyloid levels in Alzheimer's disease.

Fonteh AN, Ormseth C, Chiang J, Cipolla M, Arakaki X, Harrington MG - PLoS ONE (2015)

Sphingolipid levels are altered in Alzheimer’s disease.Levels of SPs in SF or NP were determined using LC-MS/MS. Fig 3A, 3B, 3C, and 3D are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in SF for CN, MCI or AD subjects. Fig. 3E, 3F, 3G, and 3H are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in NP for CN, MCI or AD subjects. Group comparisons were performed using Kruskal Wallis test and non-parametric comparisons using Mann Whitney test and differences between cognitive groups indicated when P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418746&req=5

pone.0125597.g003: Sphingolipid levels are altered in Alzheimer’s disease.Levels of SPs in SF or NP were determined using LC-MS/MS. Fig 3A, 3B, 3C, and 3D are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in SF for CN, MCI or AD subjects. Fig. 3E, 3F, 3G, and 3H are the levels (mean ± SEM) of SM, Cer, dhCer, and the ratio SM/Cer in NP for CN, MCI or AD subjects. Group comparisons were performed using Kruskal Wallis test and non-parametric comparisons using Mann Whitney test and differences between cognitive groups indicated when P < 0.05.
Mentions: We next quantified the abundance of SP classes in SF from CN, MCI and AD. Although mean SM levels in all three clinical groups were similar, we noticed a slight decrease in MCI and AD (Fig 3A). Levels of Cer and dhCer were not different when comparing CN to MCI (Fig 3B and 3C). In contrast, there was an increase in Cer and dhCer in AD (Fig 3B and 3C). The slight decrease in SM (-7.3% for AD) concomitant with the increase in Cer (21.8% for AD) in CSF was more evident when we compared the ratio SM/Cer in CN to that of AD (Fig 3D). A similar study examining SP changes in NP fractions revealed a decrease in the mean levels of SM (Fig 3E), Cer (Fig 3F, P < 0.05) and dhCer (Fig 3G) in AD compared with CN such that the ratio SM/Cer did not change (Fig 3H).

Bottom Line: In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction.The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants.In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.

ABSTRACT
Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.

No MeSH data available.


Related in: MedlinePlus