High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 08/2008; 106(1):475-85. DOI: 10.1111/j.1471-4159.2008.05415.x
Source: PubMed


Recent findings suggest that hypercholesterolemia may contribute to the onset of Alzheimer's disease-like dementia but the underlying mechanisms remain unknown. In this study, we evaluated the cognitive performance in rodent models of hypercholesterolemia in relation to neuroinflammatory changes and amyloid precursor protein (APP) processing, the two key parameters of Alzheimer's disease pathogenesis. Groups of normal C57BL/6 and low density lipoprotein receptor (LDLR)-deficient mice were fed a high fat/cholesterol diet for an 8-week period and tested for memory in a radial arm maze. It was found that the C57BL/6 mice receiving a high fat diet were deficient in handling an increasing working memory load compared with counterparts receiving a control diet while the hypercholesterolemic LDLR-/- mice showed impaired working memory regardless of diet. Immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampi from high fat-fed C57BL/6 mice and LDLR-/- mice. Consistent with a neuroinflammatory response, the hyperlipidemic mice showed increased expression of cytokines/mediators including tumor necrosis factor-alpha, interleukin-1beta and -6, nitric oxide synthase 2, and cycloxygenase 2. There was also an induced expression of the key APP processing enzyme i.e. beta-site APP cleaving enzyme 1 in both high fat/cholesterol-fed C57BL/6 and LDLR-/- mice accompanied by an increased generation of C-terminal fragments of APP. Although ELISA for beta-amyloid failed to record significant changes in the non-transgenic mice, a threefold increase in beta-amyloid 40 accumulation was apparent in a strain of transgenic mice expressing wild-type human APP on high fat/cholesterol diet. The findings link hypercholesterolemia with cognitive dysfunction potentially mediated by increased neuroinflammation and APP processing in a non-transgenic mouse model.

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Available from: Kumar Sambamurti, Oct 24, 2014
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    • "Elevated levels of cholesterol have been proposed as one of the midlife risk factors for developing Alzheimer's disease [2]. It has been shown that hypercholesterolemia induced by diet can produce neuroinflammation accompanied by cognitive deficit as well as changes in the processing of amyloid precursor protein (APP) one of the markers associate to Alzheimer's disease in C57BL/6 mice [3]. In apolipoprotein E ε3 and ε4 knock-in mice 44 -45 weeks of cholesterol enriched diet increases levels of brain cholesterol esters especially in APOE ε4 knock-in mice [4]. "
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    ABSTRACT: Nutritional intake is a fundamental determinant of health. It is well known that cholesterol rich diets can induce several pathological conditions but detailed mechanism underlying these re-mains unknown. Wistar rats, an animal strain widely used in the research have been employed to study the effects of dietary interventions due to their metabolic characteristics, which are closer to the human compared to mice. The effect of some components of the western diet, combined with cholesterol in the lipid profile have been studied, but the impact of only cholesterol or fatty-acid diets in such a profile has not been yet characterized. Here we measured the effect of 6 or 16 weeks of dietary intervention with cholesterol enriched diet (CED) or fatty-acid diet (FAD) on chol-esterol, triglyceride levels, high density lipoproteins (HDL) and low density lipoproteins (LDL). We observed significant differences in body weight only in animals treated with CED or FAD from Week 9 onwards as compared to animals fed the control diet. There were no differences between animals fed with CED or FAD in cholesterol levels at any time point nevertheless, triglyceride le-vels were significantly increased as compared to control diet in animals under both diets at early time points. Finally, both CED and FAD induced a decrease in HDL as compared to control levels in treatments of more than 6 weeks, whereas LDL transiently increased in animals treated with FAD from 10 to 12 weeks, but after this period LDL levels returned to baseline, suggesting that young rats have a compensatory effect at least for the period of time analyzed here. Here we provide a temporal course on lipid profile of cholesterol, triglycerides, HDL and LDH in Wistar rats treated with CED and FAD diet that can be useful as reference for future studies.
    Advances in Bioscience and Biotechnology 09/2014; 5(10):846-852. DOI:10.4236/abb.2014.510099
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    • "Obesity is a disease in which low grade inflammation is described at the periphery both in humans and rodent models (Clement et al., 2004; Cottam et al., 2004; Everard and Cani, 2013). In rodents, obesity-induced inflammation is also described at the brain level and, of interest for spatial memory, in the hippocampus (Dinel et al., 2011; Lu et al., 2011; Thirumangalakudi et al., 2008). In the present study, we do not find any effects of HFD exposure on peripheral or brain pro-inflammatory cytokines production at basal state. "
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    ABSTRACT: In addition to metabolic and cardiovascular disorders, obesity pandemic is associated with chronic low-grade inflammation as well as adverse cognitive outcomes. However, the existence of critical periods of development that differ in terms of sensitivity to the effects of diet-induced obesity remains unexplored. Using short exposure to a high-fat diet (HFD) exerting no effects when given to adult mice, we recently found impairment of hippocampal-dependent memory and plasticity after similar HFD exposure encompassing adolescence (from weaning to adulthood) showing the vulnerability of the juvenile period (Boitard et al., 2012). Given that inflammatory processes modulate hippocampal functions, we evaluated in rats whether the detrimental effect of juvenile HFD (jHFD) on hippocampal-dependent memory is associated with over-expression of hippocampal pro-inflammatory cytokines. jHFD exposure impaired long-term spatial reference memory in the Morris water maze without affecting acquisition or short-term memory. This suggests an effect on consolidation processes. Moreover, jHFD consumption delayed spatial reversal learning. jHFD intake did neither affect basal expression of pro-inflammatory cytokines at the periphery nor in the brain, but potentiated the enhancement of Interleukin-1-beta and Tumor Necrosis Factor-alpha expression specifically in the hippocampus after a peripheral immune challenge with lipopolysaccharide. Interestingly, whereas the same duration of HFD intake at adulthood induced similar weight gain and metabolic alterations as jHFD intake, it did neither affect spatial performance (long-term memory or reversal learning) nor lipopolysaccharide-induced cytokine expression in the hippocampus. Finally, spatial reversal learning enhanced Interleukin-1-beta in the hippocampus, but not in the frontal cortex and the hypothalamus, of jHFD-fed rats. These results indicate that juvenile HFD intake promotes exaggerated pro-inflammatory cytokines expression in the hippocampus which is likely to contribute to spatial memory impairment.
    Brain Behavior and Immunity 08/2014; 40. DOI:10.1016/j.bbi.2014.03.005 · 5.89 Impact Factor
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    • "Nowadays, poorly composed diet is a factor causing many lifestyle diseases in people, especially in the elderly. For example, the diet rich in monosaccharides or saturated fats is the cause of accelerated dementia development in the elderly people in Alzheimer's disease [15] [16]. "
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    ABSTRACT: Aronia juice is considered to be a source of compounds with high antioxidative potential. We conducted a study on the impact of compounds in the Aronia juice on oxidative stress in plasma and brain tissues. The influence of Aronia juice on oxidative stress parameters was tested with the use of a model with a high content of fructose and nonsaturated fats. Therefore, the activity of enzymatic (catalase, CAT, and paraoxonase, PON) and nonenzymatic (thiol groups, SH, and protein carbonyl groups, PCG) oxidative stress markers, which indicate changes in the carbohydrate and protein profiles, was marked in brain tissue homogenates. Adding Aronia caused statistically significant increase in the CAT activity in plasma in all tested diets, while the PON activity showed a statistically significant increase only in case of high fat diet. In animals fed with Aronia juice supplemented with carbohydrates or fat, statistically significant increase in the PON activity and the decrease in the CAT activity in brain tissue were observed. In case of the high fat diet, an increase in the number of SH groups and a decrease in the number of PCG groups in brain tissue were observed.
    BioMed Research International 06/2014; 2014:457085. DOI:10.1155/2014/457085 · 1.58 Impact Factor
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