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Diet-induced elevations in serum cholesterol are associated with alterations in hippocampal lipid metabolism and increased oxidative stress

Cellular and Molecular Neuroscience Section, Laboratory of Neurosciences, National Institute on Aging, Biomedical Research Center, Baltimore, Maryland, USA.
Journal of Neurochemistry (Impact Factor: 4.24). 06/2011; 118(4):611-5. DOI: 10.1111/j.1471-4159.2011.07351.x
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ABSTRACT The structure and function of the hippocampus, a brain region critical for learning and memory, is impaired by obesity and hyperlipidemia. Peripheral cholesterol and sphingolipids increase progressively with aging and are associated with a range of age-related diseases. However, the mechanisms linking peripheral cholesterol metabolism to hippocampal neuroplasticity remain poorly understood. To determine whether diets that elevate serum cholesterol influence lipid metabolism in the hippocampus, we maintained rats on a diet with high amounts of saturated fat and simple sugars for 3 months and then analyzed hippocampal lipid species using tandem mass spectrometry. The high fat diet was associated with increased serum and liver cholesterol and triglyceride levels, and also promoted cholesterol accumulation in the hippocampus. Increases in hippocampal cholesterol were associated with elevated galactosyl ceramide and sphingomyelin. To determine whether changes in lipid composition exerted biological effects, we measured levels of the lipid peroxidation products 4-hydroxynonenal-lysine and 4-hydroxynonenal-histidine; both were increased locally in the hippocampus, indicative of cell membrane-associated oxidative stress. Taken together, these observations support the existence of a potentially pathogenic relationship between dietary fat intake, peripheral cholesterol and triglyceride levels, brain cell sphingolipid metabolism, and oxidative stress.

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    • "Likewise, CCP learning that involves only a single environmental cue requires only the amygdala and is independent of the DH (McDonald and White, 1993). Therefore, based on previous research that has demonstrated that the hippocampus appears to be specifically impaired by consumption of a HFD (Lindqvist et al., 2006; Kanoski et al., 2010; Stranahan et al., 2011; Valladolid-Acebes et al., 2012), we hypothesized that the multiple-cue versions of the LCP and CCP tasks would be impaired by consumption of a HFD relative to a control diet, but the single-cue versions of the two tasks would not be impaired due to the fact that they are independent of the DH. "
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    • "In addition, the single most important genetic risk factor for late-onset sporadic AD is the presence of the í µí¼€4 allele of the apolipoprotein E (apoE), the major brain lipoprotein, which mediates transport of cholesterol and other lipids [18] [19]. Epidemiological and animal studies suggested that a high-fat diet is a serious risk factor for the development of the disease, as it may elevate peripheral cholesterol, perturbate central lipid metabolism, and increase oxidative stress [20] [21] [22] [23] [24]. Among different lipid classes, ceramides have attracted much attention in recent years as key contributors in the pathology of AD as they are able to affect both Aí µí»½ generation and tau phosphorylation [25] [26]. "
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    • "In our study, as in the work by Stranahan et al. (2011), changes in the serum lipid profile mirror the lipid profile changes in the hippocampus, although a clear link has not yet been established. The DRinduced increase of desmosterol in the serum of old animals is more significant in the light of the recent findings of Sato et al. (2012). "
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