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
Source: PubMed

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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Available from: Roy G Cutler, Jul 07, 2015
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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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    ABSTRACT: Two experiments were conducted to evaluate the effects of a high-fat diet (HFD) on two tasks that were either dependent on the dorsal hippocampus (DH) or independent of the DH. A total of 80 adult male Sprague Dawley rats were administered either a lard-based HFD (60% of calories from fat) or a control diet (10% of calories from fat) for 8 weeks, and then were trained and tested on either the latent cue preference (LCP) task or the conditioned cue preference (CCP) task in a 3-compartment box apparatus (2 end-compartments and 1 middle-compartment). The end compartments of the box apparatus contained either a single environmental cue (DH-independent) or multiple environmental cues (DH-dependent). During training trials for the LCP and CCP tasks, on alternating days, rats were given access to water in 1 of the 2 end compartments and no water in the opposite end compartment. Rats were water-replete during LCP training and were water-deprived during CCP training. During testing for both tasks, all rats were water-deprived and given free access to all compartments while the amounts of time spent in each compartment were recorded. Results showed that rats given the HFD demonstrated no compartment preferences during both LCP and CCP testing when the compartments contained multiple cues, while rats fed the control diet demonstrated normal compartment preference behavior. However, when the compartments contained a single environmental cue, rats given either the HFD and control diet demonstrated normal LCP and CCP learning. These results demonstrate that consumption of a HFD disrupted both LCP and CCP learning in a multiple-cue (DH-dependent) environment, but did not impair either type of learning in a single-cue (DH-independent) environment. This may be due to selective impairment of the DH caused by increased oxidative stress, inflammation, and/or disrupted neurotransmission produced by consumption of the HFD. This article is protected by copyright. All rights reserved.
    Hippocampus 05/2015; DOI:10.1002/hipo.22476 · 4.30 Impact Factor
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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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    ABSTRACT: Alzheimer’s disease (AD), the most common chronic and progressive neurodegenerative disorder, is characterized by extracellular deposits of amyloid β-peptides (Aβ) and intracellular deposits of hyperphosphorylated tau (phospho-tau) protein. Ceramides, the major molecules of sphingolipid metabolism and lipid second messengers, have been associated with AD progression and pathology via Aβ generation. Enhanced levels of ceramides directly increase Aβ through stabilization of β-secretase, the key enzyme in the amyloidogenic processing of Aβ precursor protein (APP). As a positive feedback loop, the generated oligomeric and fibrillar Aβ induces a further increase in ceramide levels by activating sphingomyelinases that catalyze the catabolic breakdown of sphingomyelin to ceramide. Evidence also supports important role of ceramides in neuronal apoptosis. Ceramides may initiate a cascade of biochemical alterations, which ultimately leads to neuronal death by diverse mechanisms, including depolarization and permeabilization of mitochondria, increased production of reactive oxygen species (ROS), cytochrome c release, Bcl-2 depletion, and caspase-3 activation, mainly by modulating intracellular signalling, particularly along the pathways related to Akt/PKB kinase and mitogen-activated protein kinases (MAPKs). This review summarizes recent findings related to the role of ceramides in oxidative stress-driven neuronal apoptosis and interplay with Aβ in the cascade of events ending in neuronal degeneration.
    Oxidative medicine and cellular longevity 01/2015; 2015:1-17. DOI:10.1155/2015/346783 · 3.36 Impact Factor
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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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    ABSTRACT: Maintaining cholesterol homeostasis in the brain is vital for its proper functioning. While it is well documented that dietary restriction modulates the metabolism of cholesterol peripherally, little is known as to how it can affect cholesterol metabolism in the brain. The present study was designed to elucidate the impact of long-term dietary restriction on brain cholesterol metabolism. Three-month-old male Wistar rats were exposed to long-term dietary restriction until 12 and 24 months of age. The concentrations of cholesterol, its precursors and metabolites, and food-derived phytosterols were measured in the serum, cortex, and hippocampus by gas chromatography/mass spectrometry. Relative changes in the levels of proteins involved in cholesterol synthesis, transport, and degradation were determined by Western blot analysis. Reduced food intake influenced the expression patterns of proteins implicated in cholesterol metabolism in the brain in a region-specific manner. Dietary restriction decreased the concentrations of cholesterol precursors, lanosterol in the cortex, and lanosterol and lathosterol in the hippocampus at 12 months, while the level of desmosterol was elevated in the hippocampus at 24 months. The concentrations of cholesterol and 24(S)-hydroxycholesterol remained unaffected. Food-derived phytosterols were significantly lower after dietary restriction in both the cortex and hippocampus at 12 and 24 months. These findings provide new insight into the effects of dietary restriction on cholesterol metabolism in the brain, lending further support to its neuroprotective effect.
    Age 04/2014; 36(3). DOI:10.1007/s11357-014-9654-z · 3.45 Impact Factor
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