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Background: Increased plasma free fatty acids (FFAs) impair insulin sensitivity in dairy cows via unknown mechanisms. In nonruminants, saturated FFAs upregulate the hepatic synthesis and secretion of ceramide, which inhibits insulin action.Objective: We aimed to determine whether an increase in plasma FFAs promotes hepatic and plasma ceramide accumulation in dairy cows.Methods: Six nonpregnant, nonlactating Holstein cows were used in a study with a crossover design and treatments consisting of intravenous infusion of either saline (control) or triacylglycerol emulsion (TG; 20 g/h) for 16 h. The feeding level was set at 120% of energy requirements. Blood was collected at regular intervals and liver was biopsied at 16 h. Ceramides, monohexosylceramides (Glc/Gal-Cer), lactosylceramides (LacCer), and sphingomyelins (SMs) in plasma and liver were profiled. Hepatic expression of ceramide synthases was determined. Data were analyzed with the use of mixed models, regressions, and Spearman rank correlations.Results: After 16 h of infusion, plasma FFA concentrations were >5-fold and liver triacylglycerol concentrations were 4-fold greater in TG cows, relative to control. Plasma total and very long-chain ceramide (e.g., C24:0-ceramide) concentrations increased ∼4-fold in TG over control by hour 16 of infusion, while C16:0-ceramide were not modified by TG. Infusion of TG increased plasma Glc/Gal-Cer (e.g., C16:0-Glc/Gal-Cer, 4-fold by hour 16) relative to control, but did not alter LacCer or SM concentrations. Hepatic ceramide concentrations increased with TG relative to control (e.g., C24:0-ceramide by 1.7-fold). Hepatic expression of ceramide synthase 2 was 60% greater after TG infusion compared with the control. Circulating ceramides were related to circulating FFA and hepatic triacylglycerol concentrations (e.g., C24:0-ceramide, ρ = 0.73 and 0.80, respectively; P < 0.001).Conclusion: Hepatic ceramide synthesis is associated with elevations in circulating FFAs and hepatic triacylglycerol during the induction of hyperlipidemia in dairy cows. This work supports the emerging evidence for the role of ceramide during hepatic steatosis and insulin antagonism in cows. [ABSTRACT FROM AUTHOR]

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 levels of sphingolipids (ceramides and sphingomyelins), amyloid-beta (Aβ1-42, AβX-38, AβX-40, and AβX-42) and tau (T-tau and p-tau181) in 91 cognitively normal individuals, aged 36–69 years, with a parental history of Alzheimer's disease. 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 cerebrospinal fluid ceramides and sphingomyelins and Aβ and tau levels in cognitively normal individuals at increased risk for Alzheimer's disease, indicating these sphingolipids may be associated with early pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: 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 are 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. [Copyright &y& Elsevier]

• Endolysosomes physically and functionally interact with other organelles. • Alterations in endolysosome structure and function are implicated in HAND and AD. • A better understanding of inter-organellar signaling might lead to improved therapeutics. Endolysosomes, mitochondria, peroxisomes, endoplasmic reticulum, and plasma membranes are now known to physically and functionally interact with each other. Such findings of inter-organellar signaling and communication has led to a resurgent interest in cell biology and an increased appreciation for the physiological actions and pathological consequences of the dynamic physical and chemical communications occurring between intracellular organelles. Others and we have shown that HIV-1 proteins implicated in the pathogenesis of neuroHIV and that Alzheimer's disease both affects the structure and function of intracellular organelles. Intracellular organelles are highly mobile, and their intracellular distribution almost certainly affects their ability to interact with other organelles and to regulate such important physiological functions as endolysosome acidification, cell motility, and nutrient homeostasis. Indeed, compounds that acidify endolysosomes cause endolysosomes to exhibit a mainly perinuclear pattern while compounds that de-acidify endolysosomes cause these organelles to exhibit a larger profile as well as movement towards plasma membranes. Endolysosome pH might be an early event in the pathogenesis of neuroHIV and Alzheimer's disease and in terms of organellar biology endolysosome changes might be upstream of HIV-1 protein-induced changes to other organelles. Thus, inter-organellar signaling mechanisms might be involved in the pathogenesis of neuroHIV and other neurological disorders, and a better understanding of inter-organellar signaling might lead to improved therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract: A blood-based biomarker of Alzheimer''s disease (AD) progression could be instrumental in targeting asymptomatic individuals for treatment early in the disease process. Given the direct connection between sphingomyelins (SM), ceramides, and apoptosis, these lipids may be indicators of neurodegeneration and AD progression. Baseline serum SM and ceramides from 100 women enrolled in a longitudinal population-based study were examined as predictors of cognitive impairment. Participants were followed up to six visits over 9 years. Baseline lipids, in tertiles, were examined in relation to cross-sectional and incident impairment (<1.5 S.D. below standard norms) on HVLT-immediate and -delayed memory recall and Trails A and B. SM and ceramides varied in relation to the timing of HVLT-delayed impairment: low levels were associated with cross-sectional impairment; high levels predicted incident impairment in asymptomatic individuals. Lipids were not associated with loss-to-follow-up. Results suggest serum SM and ceramides vary according to the timing of the onset of memory impairment and may be good pre-clinical predictors, or biomarkers, of memory impairment: a deficit observed early in AD pathogenesis. [Copyright &y& Elsevier]

• Extracellular vesicles (EVs) are potent vehicles of intercellular communication. • EVs can transport pathological cargo that contributes to disease. • One pathway of EV biogenesis is dependent upon ceramides generated by nSMase2. • Inhibition of nSMase2 shows promise in treating diseases that propagate via EVs. • Potent and selective nSMase2 inhibitors have recently been discovered. Extracellular vesicles (EVs) are indispensable mediators of intercellular communication, but they can also assume a nefarious role by ferrying pathological cargo that contributes to neurological, oncological, inflammatory, and infectious diseases. The canonical pathway for generating EVs involves the endosomal sorting complexes required for transport (ESCRT) machinery, but an alternative pathway is induced by the enrichment of lipid membrane ceramides generated by neutral sphingomyelinase 2 (nSMase2). Inhibition of nSMase2 has become an attractive therapeutic strategy for inhibiting EV biogenesis, and a growing number of small-molecule nSMase2 inhibitors have shown promising therapeutic activity in preclinical disease models. This review outlines the function of EVs, their potential role in disease, the discovery and efficacy of nSMase2 inhibitors, and the path to translate these findings into therapeutics. [ABSTRACT FROM AUTHOR]

Sphingolipids serve important structural and functional roles in cellular membranes and myelin sheaths. Plasma sphingolipids have been shown to predict cognitive decline and Alzheimer's disease. However, the association between plasma sphingolipid levels and brain white matter (WM) microstructure has not been examined. We investigated whether plasma sphingolipids (ceramides and sphingomyelins) were associated with magnetic resonance imaging-based diffusion measures, fractional anisotropy (FA), and mean diffusivity, 10.5 years later in 17 WM regions of 150 cognitively normal adults (mean age 67.2). Elevated ceramide species (C20:0, C22:0, C22:1, and C24:1) were associated with lower FA in multiple WM regions, including total cerebral WM, anterior corona radiata, and the cingulum of the cingulate gyrus. Higher sphingomyelins (C18:1 and C20:1) were associated with lower FA in regions such as the anterior corona radiata and body of the corpus callosum. Furthermore, lower sphingomyelin to ceramide ratios (C22:0, C24:0, and C24:1) were associated with lower FA or higher mean diffusivity in regions including the superior and posterior corona radiata. However, although these associations were significant at the a priori p < 0.05, only associations with some regional diffusion measures for ceramide C22:0 and sphingomyelin C18:1 survived correction for multiple comparisons. These findings suggest plasma sphingolipids are associated with variation in WM microstructure in cognitively normal aging. [ABSTRACT FROM AUTHOR]

Abstract: The increased life expectancy of people living with HIV-1/AIDS is accompanied by increased prevalence of HIV–1-associated neurocognitive disorder. As well, these individuals are increasingly experiencing Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased deposition of amyloid beta (Aβ) protein. Findings that Aβ production occurs largely in endolysosomes, that HIV-1 transactivator protein (Tat) disrupts endolysosome function—an early pathological feature of AD—and that HIV-1 Tat can increase Aβ levels prompted us to test the hypothesis that endolysosome dysfunction is associated with HIV-1 Tat-induced increases in neuronal Aβ generation. Using primary cultured rat hippocampal neurons, we found that treatment with HIV-1 Tat caused such morphological changes as enlargement of endolysosomes identified with LysoTracker dye and such functional changes as elevated endolysosome pH measured ratiometrically with LysoSensor dye. The HIV-1 Tat-induced changes in endolysosome function preceded temporally HIV-1 Tat-induced increases in Aβ generation measured using enzyme-linked immunosorbent assay. In addition, we demonstrated that HIV-1 Tat increased endolysosome accumulation of Aβ precursor protein and Aβ identified using immunostaining with 4G8 antibodies. Furthermore, we demonstrated that treatment of neurons with HIV-1 Tat increased endolysosome accumulation of beta amyloid-converting enzyme, the rate-limiting enzymatic step for Aβ production, and enhanced beta amyloid-converting enzyme activity. Together, our findings suggest that HIV-1 Tat increases neuronal Aβ generation and thereby contributes to the development of AD-like pathology in HIV–1-infected individuals by disturbing endolysosome structure and function. [Copyright &y& Elsevier]

Abstract: The ɛ4 allele of ApoE is associated with an earlier onset and faster progression of Alzheimer''s disease in patients with the familial form of this neurodegenerative condition. Although ApoE4 has been repeatedly associated with altered sphingomyelin and cholesterol levels in tissue culture and rodent models, there has not been a direct quantification of sphingomyelin or sterol levels in the brains of patients with different forms of ApoE. We measured the sphingolipid and sterol content of human brain tissues and found no evidence of perturbed sterol or sphingolipid biochemistry in the brains of individuals expressing ApoE4 who did not have a preexisting neurodegenerative condition. Nevertheless, ApoE4 was associated with gross abnormalities in the sterol and sphingolipid content of numerous brain regions in patients with Alzheimer''s diseaase. The findings suggest that ApoE4 may not by itself alter sterol or sphingolipid metabolism in the brain under normal conditions, but that other neuropathologic changes of Alzheimer''s are required to unmask the effect of ApoE4, and to perturb sterol and sphingolipid biochemistry. [Copyright &y& Elsevier]

[Display omitted] Extracellular Vesicles (EVs) are implicated in the spread of pathogenic proteins in a growing number of neurological diseases. Given this, there is rising interest in developing inhibitors of Neutral Sphingomyelinase 2 (nSMase2), an enzyme critical in EV biogenesis. Our group recently discovered phenyl(R)‐(1‐(3‐(3,4‐dimethoxyphenyl)‐2,6‐dimethylimidazo[1,2‐ b ]pyridazin‐8‐yl)pyrrolidin‐3‐yl)carbamate (PDDC), the first potent, selective, orally-available, and brain-penetrable nSMase2 inhibitor, capable of dose-dependently reducing EVs release in vitro and in vivo. Herein, using multiplexed Surface Plasmon Resonance imaging (SPRi), we evaluated which brain cell-derived EVs were affected by PDDC following acute brain injury. Mice were fed PDDC-containing chow at doses which gave steady PDDC brain exposures exceeding its nSMase2 IC 50. Mice were then administered an intra-striatal IL-1β injection and two hours later plasma and brain were collected. IL-1β injection significantly increased striatal nSMase2 activity which was completely normalized by PDDC. Using SPRi, we found that IL-1β-induced injury selectively increased plasma levels of CD171 + and PLP1 + EVs; this EV increase was normalized by PDDC. In contrast, GLAST1 + EVs were unchanged by IL-1β or PDDC. IL-1β injection selectively increased EVs released from activated versus non-activated microglia, indicated by the CD11b+/IB4 + ratio. The increase in EVs from CD11b + microglia was dramatically attenuated with PDDC. Taken together, our data demonstrate that following acute injury, brain nSMase2 activity is elevated. EVs released from neurons, oligodendrocytes, and activated microglial are increased in plasma and inhibition of nSMase2 with PDDC reduced these IL-1β-induced changes implicating nSMase2 inhibition as a therapeutic target for acute brain injury. [ABSTRACT FROM AUTHOR]