Sphingolipids in the membranes of neurons play important roles in signal transduction, either by modulating the localization and activation of membrane-associated receptors or by acting as precursors of bioactive lipid mediators. Activation of cytokine and neurotrophic factor receptors coupled to sphingomyelinases results in the generation of ceramides and gangliosides, which in turn, modify the structural and functional plasticity of neurons. In aging and neurodegenerative conditions such as Alzheimer's disease (AD), there is increased membrane-associated oxidative stress and excessive production and accumulation of ceramides. Studies of brain tissue samples from human subjects, and of experimental models of the diseases, suggest that perturbed sphingomyelin metabolism is a pivotal event in the dysfunction and degeneration of neurons that occurs in AD and HIV dementia. Dietary and pharmacological interventions that target sphingolipid metabolism should be pursued for the prevention and treatment of neurodegenerative disorders.

Objectives:Previous studies have shown that high serum ceramides are associated with memory impairment and hippocampal volume loss, but have not examined dementia as an outcome. The aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were associated with an increased risk of all-cause dementia and Alzheimer disease (AD).Methods: Participants included 99 women without dementia aged 70-79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry.Results: Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1-C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2-85.1) and 7.6-fold increased risk of AD (95% CI 0.9-62.1), respectively. The highest tertiles of ceramide d18:1-C24:0 (hazard ratio [HR] ϭ 5.1, 95% CI 1.1-23.6) and lactosylceramide (HR ϭ 9.8, 95% CI 1.2-80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD. Conclusions:Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies. Neurology ® 2012;79:633-641 GLOSSARY A␤ ϭ amyloid-␤; AD ϭ Alzheimer disease; amu ϭ atomic mass units; APP ϭ amyloid precursor protein; BACE-1 ϭ ␤-site APP cleaving enzyme 1; BMI ϭ body mass index; CI ϭ confidence interval; DSM-IV ϭ Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ESI-MS/MS ϭ electrospray ionization tandem mass spectrometry; HDL ϭ high-density lipoprotein; HR ϭ hazard ratio; MCI ϭ mild cognitive impairment; MMSE ϭ Mini-Mental State Examination; SM ϭ sphingomyelin; WHAS II ϭ Women's Health and Aging Study II.Lipidomic, metabolomic, and targeted approaches have identified pathways and products of sphingolipid metabolism that are altered early in the course of Alzheimer disease (AD). [1][2][3][4][5] Ceramides facilitate the regulation of ␤-site APP cleaving enzyme 1 (BACE-1) and ␥-secretase activity and amyloid precursor protein (APP) processing and trafficking. Evidence also suggests that glycosphingolipids bind amyloid-␤ (A␤) at the cell surface and form domains that facilitate the oligomerization and fibril formation of A␤. 6 -10 In addition to these roles, ceramide is aFrom the Division

Insulin resistance is a homeorhetic adaptation to parturition in dairy cows transitioning from late pregnancy to early lactation. An increase in prepartum adiposity can predispose periparturient cows to greater lipolysis and insulin resistance, thus increasing the risk for metabolic disease. Mechanisms mediating the development of insulin resistance in overweight peripartal dairy cows may depend on ceramide metabolism. The sphingolipid ceramide accumulates in plasma and tissues of overweight monogastric animals, and facilitates saturated fatty acid-induced insulin resistance. Considering this evidence, we hypothesized that plasma ceramides would be elevated in periparturient dairy cattle and that these sphingolipids would correlate with the magnitude of lipolysis and insulin resistance. To test our central hypothesis, multiparous Holstein cows were allocated into 2 groups according to their body condition score (BCS) at d −30 prepartum: lean (BCS <3.0; n = 10) or overweight (BCS >4.0; n = 11). Blood samples were collected at d −45, −30, −15, and −7, relative to expected parturition, and at d 4 postpartum. Plasma glucose, insulin, nonesterified fatty acids (NEFA), and β-hydroxybutyrate (BHBA) concentrations were measured, and insulin sensitivity was estimated. The concentrations of individual plasma ceramide and glycosylated ceramide were determined using liquid chromatography-based mass spectrometry. Results demonstrated that greater adiposity was associated with a greater loss in body condition during late pregnancy. Overweight cows had greater circulating concentrations of glucose, insulin, and NEFA, and lower insulin sensitivity relative to lean cows. We detected 30 different sphingolipids across 6 lipid classes with acyl chains ranging from 16 to 26 carbons. The most abundant plasma sphingolipids detected were C24:0-ceramide, C24:0-monohexosylceramide, and C16:0-lactosylceramide. Plasma concentrations of total ceramide and monohexosylceramide increased as lactation approached, and saturated ceramide and monohexosylceramide were elevated in cows with greater adiposity relative to those with a lean phenotype. Plasma ceramides (e.g., C24:0-ceramide) were positively correlated with plasma NEFA and inversely correlated with insulin sensitivity. Our data demonstrate a remodeled plasma sphingolipidome in dairy cows transitioning from late pregnancy to lactation characterized by a concomitant increase in plasma ceramides with the development of peripartal insulin resistance.

Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.

Cellular studies suggest sphingolipids may cause or accelerate amyloid-beta (Aβ) and tau pathology but in vivo human studies are lacking. We determined cerebrospinal fluid (CSF) levels of sphingolipids (ceramides, sphingomyelins), amyloid-beta (Aβ1–42, AβX-38, AβX-40, AβX-42) and tau (T-tau, p-tau181) in 91 cognitively normal individuals, aged 36–69 years, with a parental history of Alzheimer's disease (AD). The 18-carbon acyl chain length ceramide species was associated with AβX-38 (r = 0.312, p = 0.003), AβX-40 (r = 0.327, p = 0.002), and T-tau (r = 0.313, p = 0.003) but not with AβX-42 (r = 0.171, p = 0.106) or p-tau (r = 0.086, p = 0.418). All sphingomyelin species correlated (most p < 0.001) with all Aβ species and T-tau; many also correlated with p-tau. Results remained in regression models after controlling for age and APOE genotype. These results suggest in vivo relationships between CSF ceramides and sphingomyelins and Aβ and tau levels in cognitively normal individuals at increased risk for AD, indicating these sphingolipids may be associated with early pathogenesis.

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