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Ceramide-C16 Is a Versatile Modulator of Phosphatidylethanolamine Polymorphism.

ABSTRACT: Ceramide-C16 (CerC16) is a sphingolipid associated with several diseases like diabetes, obesity, Parkinson disease, and certain types of cancers. As a consequence, research efforts are devoted to identify the impact of CerC16 on the behavior of membranes, and to understand how it is involved in these diseases. In this work, we investigated the impacts of CerC16 (up to 20 mol %) on the lipid polymorphism of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), using differential scanning calorimetry, and sequential 2H and 31P solid-state nuclear magnetic resonance spectroscopy. A partial phase diagram is proposed. The results indicate that the presence of CerC16 leads to an upshift of the temperature of the gel-to-liquid crystalline (L? - L?) phase transition, leading to a large L?/L? phase coexistence region where gel-phase domains contain ?35 mol % CerC16. It also leads to a downshift of the temperature of the lamellar-to-inverted hexagonal (L - HII) phase transition of POPE. The opposite influence on the two-phase transitions of POPE brings a three-phase coexistence line when the two transitions overlap. The resulting HII phase can be ceramide enriched, coexisting with a L? phase, or ceramide depleted, coexisting with a L? phase, depending on the CerC16 proportions. The uncommon capability of CerC16 to modulate the membrane fluidity, its curvature propensity, and the membrane interface properties highlights its potential as a versatile messenger in cell membrane events.

SUBMITTER: Doroudgar M

PROVIDER: S-EPMC5474839 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Ceramide-C16 Is a Versatile Modulator of Phosphatidylethanolamine Polymorphism.

Doroudgar Mahmoudreza M Lafleur Michel M

Biophysical journal 20170601 11

Ceramide-C16 (CerC16) is a sphingolipid associated with several diseases like diabetes, obesity, Parkinson disease, and certain types of cancers. As a consequence, research efforts are devoted to identify the impact of CerC16 on the behavior of membranes, and to understand how it is involved in these diseases. In this work, we investigated the impacts of CerC16 (up to 20 mol %) on the lipid polymorphism of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), using differential scanning ...[more]

PMID: 28591608

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Project description:BackgroundDysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-? (A?) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.MethodsA plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-? (A?), A? aggregation process in presence of CERTL, and the resulting changes in A? toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno-associated virus (AAV) in a mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety, and locomotion. At week 12, brains were investigated for sphingolipid levels by mass spectrometry, plaques, and neuroinflammation by immunohistochemistry, gene expression, and/or immunoassay.ResultsHere, we report that CERTL binds to APP, modifies A? aggregation, and reduces A? neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTL in vivo over-expression has a mild effect on animal locomotion, decreases A? formation, and modulates microglia by decreasing their pro-inflammatory phenotype.ConclusionOur results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

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Ceramide-C16 Is a Versatile Modulator of Phosphatidylethanolamine Polymorphism.

Publications

Ceramide-C16 Is a Versatile Modulator of Phosphatidylethanolamine Polymorphism.

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