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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

Scheme highlighting the role of perturbed sphingolipid metabolism in Alzheimer’s disease pathology.A) Pro-aSMase is distributed between the Golgi secretory pathway and the lysosomal pathway. B) SMase, ceramidase and phospholipases can induce the formation of secretory vesicles or blebbing of plasma membranes to generate nano- or micro-sized particles with different SP composition. C) Secreted aSMase (S-aSMase) plays a role in endocytosis, membrane repair or remodeling. D) Endocytosis mediated by aSMase influences amyloid precursor protein processing and the concentration of Aβ. E) Lysosomal aSMase (L-aSMase) plays a role in the fusion of phagophores with lysosomes, resulting in autophagocytosis (F). Any dysfunction in this sphingolipid metabolic pathway, such as the decrease in secretory aSMase in AD, will result in changes in the physical properties of cellular membranes, anomaly in exocytosis/endocytosis, defective trafficking of lipids and membrane-anchored proteins, resulting in dysfunctional membrane repair, and altered Aβ excretion. Abbreviations used on Fig 7. GP, glycerophospholipids; SM, sphingomyelin; Cer, ceramide; S_aSMase, secretory acid sphingomyelinase; L_aSMase, lysosomal acid sphingomyelinase; mb_nSMase, membrane bound neutral sphingomyelinase; APP, amyloid precursor protein.
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pone.0125597.g007: Scheme highlighting the role of perturbed sphingolipid metabolism in Alzheimer’s disease pathology.A) Pro-aSMase is distributed between the Golgi secretory pathway and the lysosomal pathway. B) SMase, ceramidase and phospholipases can induce the formation of secretory vesicles or blebbing of plasma membranes to generate nano- or micro-sized particles with different SP composition. C) Secreted aSMase (S-aSMase) plays a role in endocytosis, membrane repair or remodeling. D) Endocytosis mediated by aSMase influences amyloid precursor protein processing and the concentration of Aβ. E) Lysosomal aSMase (L-aSMase) plays a role in the fusion of phagophores with lysosomes, resulting in autophagocytosis (F). Any dysfunction in this sphingolipid metabolic pathway, such as the decrease in secretory aSMase in AD, will result in changes in the physical properties of cellular membranes, anomaly in exocytosis/endocytosis, defective trafficking of lipids and membrane-anchored proteins, resulting in dysfunctional membrane repair, and altered Aβ excretion. Abbreviations used on Fig 7. GP, glycerophospholipids; SM, sphingomyelin; Cer, ceramide; S_aSMase, secretory acid sphingomyelinase; L_aSMase, lysosomal acid sphingomyelinase; mb_nSMase, membrane bound neutral sphingomyelinase; APP, amyloid precursor protein.

Mentions: Our data show that higher aSMase activity corresponds to higher Aβ42 in CSF from CN participants. Similarly, lower aSMase activity in the CSF from AD corresponds to lower Aβ42 levels compared with CN. aSMase activity significantly correlates with Aβ42 levels in CN but not in MCI or AD while no similar correlation is found for nSMase or to total tau protein. These data suggest that aSMase activity in CSF may be involved in the secretion of Aβ42 in health, thus preventing the accumulation of neurotoxic peptides in brain tissues. A scheme depicting how lower activities of aSMase may result in lower Aβ42 levels in CSF and higher plaque load in AD brain tissues is shown on Fig 7. This scheme suggests that dysfunction in SP metabolism in AD alters exocytosis/endocytosis at many sites. Amyloid precursor protein processing may be adversely affected in at least 6 locations: 7A) Pro-aSMase is distributed between the Golgi secretory pathway and the lysosomal pathway. Defective proteolytic maturation of SMase can lead to dysfunction and abnormal SM metabolism found in lipid storage disease [16]. This might result in the difference in sphingolipid metabolism that we report in CSF fractions from our AD subjects. The lower amounts of soluble aSMase found in AD will lower enzyme activity and compromise SM metabolism. 7B) Since aSMase [68,69], ceramidase [70] and phospholipase A2 [71–73] are implicated in secretory vesicle formation and membrane restructuring, decreased aSMase that we measured in AD may impact membrane remodeling and the generation of nano- or micro-sized particles, such as those in the NP fraction of CSF. Increased phospholipase A2 activity that we recently reported in CSF from AD subjects [41] may also modify membrane lipids. Any such modification of membrane composition will result in a shift in the physical properties of cellular membranes, anomaly in exocytosis, defective trafficking of lipids, and altered distribution of membrane-anchored proteins [74]. 7C) Secreted aSMase plays a role in endocytosis, membrane repair or remodeling [66]. Thus a decrease in aSMase that we measured in AD will reduce these processes and alter membrane properties and function. 7D) Brain aSMase and S1P levels correlate with amyloid beta peptide and hyperphosphorylated tau protein levels [75]. Both aSMase and nSMase mediated-endocytosis influence APP processing and thus regulate Aβ42 concentration [57,75], and influence membrane properties when they interact with components of lipid rafts. Lower aSMase activity in CSF from AD subjects will decrease APP processing and lower the ability of brain cells to clear toxic Aβ42. 7E) Lysosomal aSMase is important in autophagocytosis when phagophores fuse with lysosomes [76]. Less aSMase or improperly processed aSMase in AD will result in lowered endocytosis. 7F) aSMase plays a role in autophagocytosis, a process where denatured or oxidized DNA, lipids, and proteins such as Aβ42 that would otherwise be toxic to brain cells are digested and neutralized for resorption [77]. The lower aSMase activity in AD will result in less clearance of toxic products such as Aβ42, resulting in Aβ42 accumulation and neuronal death. In summary, a hallmark of AD pathology is the dysfunction of SP metabolism which impacts membrane remodeling and results in the abnormal clearance of neurotoxic Aβ42 peptides. Means of enhancing the secretion of Aβ42 from brain tissue may limit its accumulation and subsequent formation of neurotoxic plaques.


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)

Scheme highlighting the role of perturbed sphingolipid metabolism in Alzheimer’s disease pathology.A) Pro-aSMase is distributed between the Golgi secretory pathway and the lysosomal pathway. B) SMase, ceramidase and phospholipases can induce the formation of secretory vesicles or blebbing of plasma membranes to generate nano- or micro-sized particles with different SP composition. C) Secreted aSMase (S-aSMase) plays a role in endocytosis, membrane repair or remodeling. D) Endocytosis mediated by aSMase influences amyloid precursor protein processing and the concentration of Aβ. E) Lysosomal aSMase (L-aSMase) plays a role in the fusion of phagophores with lysosomes, resulting in autophagocytosis (F). Any dysfunction in this sphingolipid metabolic pathway, such as the decrease in secretory aSMase in AD, will result in changes in the physical properties of cellular membranes, anomaly in exocytosis/endocytosis, defective trafficking of lipids and membrane-anchored proteins, resulting in dysfunctional membrane repair, and altered Aβ excretion. Abbreviations used on Fig 7. GP, glycerophospholipids; SM, sphingomyelin; Cer, ceramide; S_aSMase, secretory acid sphingomyelinase; L_aSMase, lysosomal acid sphingomyelinase; mb_nSMase, membrane bound neutral sphingomyelinase; APP, amyloid precursor protein.
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pone.0125597.g007: Scheme highlighting the role of perturbed sphingolipid metabolism in Alzheimer’s disease pathology.A) Pro-aSMase is distributed between the Golgi secretory pathway and the lysosomal pathway. B) SMase, ceramidase and phospholipases can induce the formation of secretory vesicles or blebbing of plasma membranes to generate nano- or micro-sized particles with different SP composition. C) Secreted aSMase (S-aSMase) plays a role in endocytosis, membrane repair or remodeling. D) Endocytosis mediated by aSMase influences amyloid precursor protein processing and the concentration of Aβ. E) Lysosomal aSMase (L-aSMase) plays a role in the fusion of phagophores with lysosomes, resulting in autophagocytosis (F). Any dysfunction in this sphingolipid metabolic pathway, such as the decrease in secretory aSMase in AD, will result in changes in the physical properties of cellular membranes, anomaly in exocytosis/endocytosis, defective trafficking of lipids and membrane-anchored proteins, resulting in dysfunctional membrane repair, and altered Aβ excretion. Abbreviations used on Fig 7. GP, glycerophospholipids; SM, sphingomyelin; Cer, ceramide; S_aSMase, secretory acid sphingomyelinase; L_aSMase, lysosomal acid sphingomyelinase; mb_nSMase, membrane bound neutral sphingomyelinase; APP, amyloid precursor protein.
Mentions: Our data show that higher aSMase activity corresponds to higher Aβ42 in CSF from CN participants. Similarly, lower aSMase activity in the CSF from AD corresponds to lower Aβ42 levels compared with CN. aSMase activity significantly correlates with Aβ42 levels in CN but not in MCI or AD while no similar correlation is found for nSMase or to total tau protein. These data suggest that aSMase activity in CSF may be involved in the secretion of Aβ42 in health, thus preventing the accumulation of neurotoxic peptides in brain tissues. A scheme depicting how lower activities of aSMase may result in lower Aβ42 levels in CSF and higher plaque load in AD brain tissues is shown on Fig 7. This scheme suggests that dysfunction in SP metabolism in AD alters exocytosis/endocytosis at many sites. Amyloid precursor protein processing may be adversely affected in at least 6 locations: 7A) Pro-aSMase is distributed between the Golgi secretory pathway and the lysosomal pathway. Defective proteolytic maturation of SMase can lead to dysfunction and abnormal SM metabolism found in lipid storage disease [16]. This might result in the difference in sphingolipid metabolism that we report in CSF fractions from our AD subjects. The lower amounts of soluble aSMase found in AD will lower enzyme activity and compromise SM metabolism. 7B) Since aSMase [68,69], ceramidase [70] and phospholipase A2 [71–73] are implicated in secretory vesicle formation and membrane restructuring, decreased aSMase that we measured in AD may impact membrane remodeling and the generation of nano- or micro-sized particles, such as those in the NP fraction of CSF. Increased phospholipase A2 activity that we recently reported in CSF from AD subjects [41] may also modify membrane lipids. Any such modification of membrane composition will result in a shift in the physical properties of cellular membranes, anomaly in exocytosis, defective trafficking of lipids, and altered distribution of membrane-anchored proteins [74]. 7C) Secreted aSMase plays a role in endocytosis, membrane repair or remodeling [66]. Thus a decrease in aSMase that we measured in AD will reduce these processes and alter membrane properties and function. 7D) Brain aSMase and S1P levels correlate with amyloid beta peptide and hyperphosphorylated tau protein levels [75]. Both aSMase and nSMase mediated-endocytosis influence APP processing and thus regulate Aβ42 concentration [57,75], and influence membrane properties when they interact with components of lipid rafts. Lower aSMase activity in CSF from AD subjects will decrease APP processing and lower the ability of brain cells to clear toxic Aβ42. 7E) Lysosomal aSMase is important in autophagocytosis when phagophores fuse with lysosomes [76]. Less aSMase or improperly processed aSMase in AD will result in lowered endocytosis. 7F) aSMase plays a role in autophagocytosis, a process where denatured or oxidized DNA, lipids, and proteins such as Aβ42 that would otherwise be toxic to brain cells are digested and neutralized for resorption [77]. The lower aSMase activity in AD will result in less clearance of toxic products such as Aβ42, resulting in Aβ42 accumulation and neuronal death. In summary, a hallmark of AD pathology is the dysfunction of SP metabolism which impacts membrane remodeling and results in the abnormal clearance of neurotoxic Aβ42 peptides. Means of enhancing the secretion of Aβ42 from brain tissue may limit its accumulation and subsequent formation of neurotoxic plaques.

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