Serum ceramides increase the risk of Alzheimer disease The Women's Health and Aging Study II

Division of Epidemiology, College of Medicine, Mayo Clinic, Rochester, MN, USA.
Neurology (Impact Factor: 8.29). 07/2012; 79(7):633-41. DOI: 10.1212/WNL.0b013e318264e380
Source: PubMed


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).
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.
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] = 5.1, 95% CI 1.1-23.6) and lactosylceramide (HR = 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.
Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies.

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    • "We envision that, during long-term exposure to ceramides, hippocampal neurons could eventually become more sensitive to excitotoxic damage, a scenario that will require further exploration. In view of the emerging involvement of ceramides in neurodegenerative disorders, such as Farber's disease [24] and Alzheimer's disease [43], our observations support the notion that prevention of these lipids formation might provide potential novel therapeutic approaches promoting neuronal survival [46]. However, evaluation of ceramide levels within hippocampal slices was not performed in the course of the present study. "
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    ABSTRACT: The lysosomal acid ceramidase, an enzyme known to limit intracellular ceramide accumulation, has been reported to be defective in neurodegenerative disorders. We show here that rat hippocampal slices, preincubated with the acid ceramidase inhibitor (ACI) d-NMAPPD, exhibit increased N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory postsynaptic potentials (fEPSPs) in CA1 synapses. The ACI by itself did not interfere with either paired pulse facilitation or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated fEPSPs, indicating that its influence on synaptic transmission is postsynaptic in origin and specific to the NMDA subtype of glutamate receptors. From a biochemical perspective, we observed that Tau phosphorylation at the Ser262 epitope was highly increased in hippocampal slices preincubated with the ACI, an effect totally prevented by the global NMDA receptor antagonist D/L(-)-2-amino-5-phosphonovaleric acid (AP-5), the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), and the GluN2B (but not the GluN2A) receptor antagonist RO25-6981. On the other hand, preincubation of hippocampal slices with the compound KN-62, an inhibitor known to interfere with calcium/calmodulin-dependent protein kinase II (CaMKII), totally abolished the effect of ACI on Tau phosphorylation at Ser262 epitopes. Collectively, these results provide experimental evidence that ceramides play an important role in regulating Tau phosphorylation in the hippocampus via a mechanism dependent on GluN2B receptor subunits and CaMKII activation.
    Neural Plasticity 09/2014; 2014:196812. DOI:10.1155/2014/196812 · 3.58 Impact Factor
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    • "Cholesterol, sphingomyelin, and ceramide are important components of lipid rafts, and reduced sphingomyelin and increased ceramide levels have been observed in AD plasma [97]. Very recently, subjects in the middle and highest tertiles of ceramide at baseline had a 10 and 7.6-fold increased risk of AD, respectively [98]. However, another study indicated that ceramide only predicted cognitive decline and neuronal loss in subjects with MCI [99]. "
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    Biochimica et Biophysica Acta 04/2014; 1842(9). DOI:10.1016/j.bbadis.2014.04.012 · 4.66 Impact Factor
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    • "Future prospective longitudinal studies with adequate power are needed to explore the association between plasma ceramides and memory performance and change in VO2peak in subjects with CAD. In addition, the sensitivity and specificity of C22:0 and C24:0 as possible plasma biomarkers of cognitive response in CAD should be assessed in future studies; however, C22:0 and C24:0 may be particularly important as they have been prospectively associated with dementia [11]. "
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    BMC Geriatrics 12/2013; 13(1):135. DOI:10.1186/1471-2318-13-135 · 1.68 Impact Factor
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