The effect of APOE genotype on brain levels of oxysterols in young and old human APOE ε2, ε3 and ε4 knock-in mice

Despite apolipoprotein E's important role in cholesterol transport and metabolism in the brain as well as its influence on Alzheimer's disease, the impact of the human APOE genotype on cholesterol metabolism in brain has not been fully examined. This study was carried out to investigate APOE genotype effects on oxysterols measured. In this study the measurement of cholesterol and several oxysterols in the brains of human APOE ε2, ε3 and ε4 knock-in mice at 8 weeks and 1 year of age using gas chromatography mass spectrometry (GC–MS) demonstrated no APOE genotype or age effect on total brain cholesterol and the oxysterol 24-hydroxycholesterol. The level of 27-hydroxycholesterol was elevated in 1 year old animals for all APOE genotypes. Interestingly, lathosterol an indicator of cholesterol synthesis was significantly reduced in the 1 year old animals for all APOE genotypes. APOE ε4 expressing mice exhibited statistically lower levels of lathosterol compared to APOE ε2 in both the young and old mice. Oxidized cholesterol metabolites were significantly lower in APOE ε2 mice compared to other genotypes at 8 weeks old. Although minimal differences were observed between APOE E3 and E4 knock-in (KI) mice, these findings indicate that there are some clear APOE genotype specific effects on brain cholesterol synthesis and associated metabolic pathways, particularly in APOE ε2 KI mice.     

Omega-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression

Long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may slow cognitive decline. The ε4 allele of the ApolipoproteinE (ApoE), the main genetic risk factor for Alzheimer's disease, and depressive symptoms, which are frequently associated with cognitive impairment in older persons, may modify this relationship. We estimated the associations between EPA and DHA plasma levels and subsequent cognitive decline over 7 years, taking into account ApoE-ε4 status and depressive symptoms, in a prospective population-based cohort. Participants (≥ 65 years, n = 1,228 nondemented at baseline) were evaluated at least once over three follow-up visits using four cognitive tests. Plasma EPA was associated with slower decline on Benton Visual Retention Test (BVRT) performances in ApoE-ε4 carriers, or in subjects with high depressive symptoms at baseline. Plasma DHA was associated with slower decline on BVRT performances in ApoE-ε4 carriers only. EPA and DHA may contribute to delaying decline in visual working memory in ApoE-ε4 carriers. In older depressed subjects, EPA, but not DHA, may slow cognitive decline.     

ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice

Protein translation is regulated during both initiation and elongation phases to enable cells to accommodate for ever-changing environmental and internal states. Eukaryotic initiation factor-2 (eIF2)α, a major signaling pathway for responses to metabolic stress, controls translation initiation in various cells, including neurons, and affects cognitive functions. The main risk factor for sporadic Alzheimer's disease (SAD) is aging, and the main genetic risk factor reducing the age of SAD onset is the expression of apolipoprotein E (ApoE)4. We tested the hypothesis that both genetic and aging risk factors converge on the eIF2α pathway. Aged rodents showed increased eIF2α phosphorylation in the brain, indicating a shift in the rate of translation initiation with increasing age. Interestingly, mice overexpressing human ApoE4 already, at an early age, exhibited increased eIF2α phosphorylation together with mild impairment in cognitive tasks, compared with ApoE3 mice. These results suggest that the eIF2α pathway is linked to SAD, possibly via genetic as well as prolonged metabolic stress, and these findings position it as a new and important target for treatment of the currently incurable Alzheimer's disease.     

Association between the PPARα-L162V polymorphism and components of the metabolic syndrome

Genetic factors, alone or in interaction with components of the diet, are thought to be involved in the development of the metabolic syndrome. The objective of our study was first to compare the frequency of the peroxisome proliferator-activated receptor (PPAR)-L162V polymorphism in a sample of men with and without the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) guidelines, and secondly, to evaluate gene–diet interaction effects on features of the metabolic syndrome. The PPAR-L162V genotype was determined in a sample of 632 men by a polymerase chain reaction–restriction length polymorphism (PCR–RFLP)-based method; fat as well as saturated fat intakes were evaluated by a dietitian-administered food frequency questionnaire. The frequency of the V162 allele was similar in men with (n=281) and without (n=351) the metabolic syndrome ( ²=0.03, p=0.84) but was higher in subjects having simultaneously abdominal obesity, hypertriglyceridemia, and low high-density lipoprotein cholesterol (HDL-C) levels ( ²=3.73, p=0.05). Carriers of the V162 were characterized by higher plasma apolipoprotein B and triglyceride (TG) levels (p=0.10, p=0.004). In a model including the PPAR-L162V polymorphism, fat or saturated fat, its interaction, and covariates (smoking habits, and energy and alcohol intake), the interaction explained a significant percentage of the variance observed in waist circumference (p<0.05). In conclusion, the PPAR-L162V polymorphism alone or in interaction with dietary fat intake is associated with components of the metabolic syndrome.     

Abnormal event-related potentials in young and middle-aged adults with the ApoE ε4 allele

The largest genetic susceptibility factor for Alzheimer's disease is the Apolipoprotein E (ApoE) ε4 allele. Cognitive decline and olfactory impairment are greater in those positive for the ε4 allele. This study sought to determine if the olfactory event-related potential (OERP), compared to the visual ERP, would be sensitive to these subtle declines. Participants included 40 individuals from two age groups, half of each group were ε4 allele positive and half were ε4 negative. Visual ERPs did not demonstrate significant differences between ApoE groups. OERPs demonstrated robust age by ApoE interactions. P3 latencies were significantly longer in ε4 young and middle age participants. These findings suggest that very early olfactory and cognitive changes related to ApoE status are detectible via the OERP.     

APOE ε4 is associated with longer telomeres, and longer telomeres among ε4 carriers predicts worse episodic memory

Both leukocyte telomere length and the apolipoprotein ε4 allele have been associated with mortality, cardiovascular disease, cognition, and dementia. The authors investigated whether leukocyte telomere length was associated with APOE genotype or cognitive abilities in the context of APOE genotype. The setting for this cross-sectional study was 427 nondemented individuals aged 41-81 yr. The authors found that ε4 carriers overall exhibited significantly longer telomeres compared with non-carriers (difference of 268 bp, p = 0.001). This difference was greatest at the lower limit of the age span and nonsignificant at the upper limit, which translated into a significantly higher telomere attrition rate (p = 0.049) among ε4 carriers (37 bp/years) compared with non-carriers (21 bp/year). Further, longer telomeres among ε4 carriers significantly predicted worse performance on episodic memory tasks. No significant associations were found on tasks tapping semantic and visuospatial ability, or among ε3/ε3 carriers. In conclusion, APOE ε4 carriers had longer telomeres compared with non-carriers, but higher rate of attrition. Among them, longer telomeres predicted worse performance on episodic memory tasks. These observations suggest that the ε4 allele is associated with abnormal cell turnover of functional and possibly clinical significance.     

Lack of association between PICALM rs3851179 polymorphism and Alzheimer's disease in Chinese population and APOEε4-negative subgroup

Recently, the association between PICALM rs3851179 polymorphism and Alzheimer's disease (AD) was investigated in the Chinese population by 3 independent studies. However, both allele and genotype tests failed to reveal any association. The association was identified only in the APOEε4-negative subgroup. We think that the failure to replicate the association may be because of the relatively small sample size. In this research, we reinvestigated the association using all the samples from these 3 studies (n = 2486, and 1202 cases and 1284 control subjects). We failed to replicate this association between the rs3851179 polymorphism and AD in all samples and the APOEε4-negative subgroup. Our results indicate that rs3851179 may not be an AD susceptibility locus in the Chinese population and the APOEε4-negative subgroup.     

Similar promotion of Aβ1-42 fibrillogenesis by native apolipoprotein E ε3 and ε4 isoforms

The apolipoprotein E ε4 allele contributes to the genetic susceptibility underlying a large proportion (~40–60%) of typical, sporadic Alzheimer disease. Apolipoprotein E deficient mice made transgenic for human apolipoprotein E ε4 accumulate excess cerebral amyloid when compared to similarly prepared mice expressing human apolipoprotein E ε3. Therefore, it is important to search for relevant interactions(s) between apolipoprotein E ε4 and Aβ in order to clarify the biological role for apolipoprotein E ε4 in Alzheimer disease. Using a thioflavine T (ThT)-based assay, we have investigated the effects of native human apolipoprotein E isoforms on the kinetics of Aβ fibrillogenesis. No obvious profibrillogenic activity was detected in Aβ_1-40-based assays of any native apolipoprotein E isoform. However, when ThT assays were repeated using Aβ_1-42, modest, but statistically significant, profibrillogenic activity was detected in both apolipoprotein E ε3- and apolipoprotein E ε4-containing media and was similar in magnitude for the two isoforms. These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Aβ: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Aβ. However, the equipotent activities of the apolipoprotein E ε3 and ε4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Aβ, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors (such as metal ions, or inflammatory mediators such as reactive oxygen species, α₂-macroglobulin, apolipoprotein J, etc.) may be required for modeling in vitro the apolipoprotein E-isoform-specific-regulation of extracellular Aβ accumulation that occurs in vivo. Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Aβ or of apolipoprotein E/Aβ complexes may underlie apolipoprotein E-isoform-dependent Aβ accumulation.     

Michels syndrome, Carnevale syndrome, OSA syndrome, and Malpuech syndrome: variable expression of a single disorder (3MC syndrome)?

We report on a 3-year-old girl with Michels syndrome, a rare condition characterized by craniosynostosis, blepharophimosis, ptosis, epicanthus inversus, cleft lip/palate, abnormal supra-umbilical abdominal wall, and mental deficiency. The phenotypic findings are compared with the six previously reported Michels cases, and with patients referred to as Carnevale, OSA, and Malpuech syndromes. Michels syndrome is characterized by cleft lip and palate, anterior chamber anomalies, blepharophimosis, epicanthus inversus, and craniosynostosis. Carnevale syndrome shows hypertelorism, downslanting palpebral fissures, ptosis, strabismus synophrys, large and fleshy ears, and lozenge-shaped diastasis around the umbilicus. OSA syndrome resembles Carnevale, with humeroradial synostoses, and spinal anomalies as extra features. Malpuech syndrome shows IUGR, hypertelorism, cleft lip and palate, micropenis, hypospadias, renal anomalies, and caudal appendage. All are autosomal recessive. Despite the presence of apparently distinctive key features, it appears that these four entities share multiple similarities in the facial Gestalt and the pattern of MCA. Those similarities lead us to postulate that they belong to the same spectrum, which could be referred to as "3MC syndrome" (Malpuech-Michels-Mingarelli-Carnevale syndrome).     

PGC-1α mRNA level and oxidative capacity of the plantaris muscle in rats with metabolic syndrome, hypertension, and type 2 diabetes

We examined the fiber profiles and the mRNA levels of peroxisome proliferator-activated receptors (PPARα and PPARδ/β) and of the PPARγ coactivator-1α (PGC-1α) in the plantaris muscles of 15-week-old control (WR), metabolic syndrome (CP), hypertensive (SHR), and type 2 diabetic (GK) rats. The deep regions in the muscles of SHR and GK rats exhibited lower percentages of high-oxidative type I and IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR and CP rats. The surface regions in the muscles of CP, SHR, and GK rats exhibited lower percentages of high-oxidative type IIA fibers and higher percentages of low-oxidative type IIB fibers compared with WR rats. The muscles of SHR and GK rats had lower oxidative enzyme activity compared with WR rats. The muscles of SHR rats had the lowest PPARδ/β mRNA level. In addition, the muscles of SHR and GK rats had lower PGC-1α mRNA level compared with WR and CP rats. We concluded that the plantaris muscles of rats with hypertension and type 2 diabetes have lower oxidative capacity, which is associated with the decreased level of PGC-1α mRNA.     

Association between metabolic syndrome and depressive symptom profiles—Sex-specific?

Background

The association between depression and metabolic syndrome is becoming more obvious. Waist circumference (WC) might be the most important metabolic syndrome (MetS) feature in relation to late-life depression, with a possible mediating role for adiponectin.

Methods

Cross-sectional population based survey of 1277 participants (50–70 years). We measured all components of MetS, plasma adiponectin levels and depressive symptoms using Beck Depression Inventory (BDI). Principal components analysis on the BDI items revealed two factors, representing a cognitive-affective and a somatic-affective symptom-cluster. Multiple linear regression models with the BDI sum score and both depression symptom-clusters as dependent variables, respectively, were used to examine the association with each component of metabolic syndrome adjusted for confounders. We explored sex-differences as well as a hypothesised mediating effect of adiponectin.

Results

The presence of MetS as well as number of metabolic risk factors were significantly associated with BDI sum score. In men WC, triglycerides and HDL cholesterol explained variance in depressive symptoms, whereas in women this effect was confined to WC. Moreover, irrespective of sex, all associations were primarily driven by the somatic-affective symptom-cluster. Adiponectin neither mediated nor moderated any of the associations found.

Limitations

Cross-sectional design limits causal interpretation. Being a population-based survey, some selection bias might have occurred toward healthier part of population.

Conclusions

Although pathophysiological mechanisms underlying the association between metabolic disturbances and depression remains to be elucidated, our study points to sex-differences as well as a specific phenotype of depression that is associated with metabolic disturbances.     

Prevalence of metabolic syndrome and related factors in bank employees according to different defining criteria,Vitória/ES,Brazil

OBJECTIVE:

To determine the prevalence of metabolic syndrome and related factors in bank employees in the city of Vitoria/ES, Brazil.

METHODS:

This was a cross-sectional study that included 521 working men and women ≥20 years of age. Sociodemographic, lifestyle, anthropometric, biochemical, and hemodynamic characteristics were collected. Metabolic syndrome was diagnosed using the criteria of the National Cholesterol Education Program-ATPIII and the International Diabetes Federation. A logistic regression model was used to calculate the crude and adjusted OR of the variables, and the statistical level of significance was set at 5.0%.

RESULTS:

We identified 86 (17.2%) and 113 (22.6%) subjects with metabolic syndrome according to the criteria of the National Cholesterol Education Program-ATPIII and the International Diabetes Federation, respectively. The risk of developing metabolic syndrome was higher in individuals with a high school education (OR 2.6 [CI_95%, 1.1-6.1]). In overweight and obese subjects, the risks were also higher (OR 12.6 [CI_95%, 4.8-33.2, p = 0.000] and OR 43.7% [CI_95%, 16.1-118.9, p = 0.000], respectively).

CONCLUSION:

A large number of bank employees have metabolic syndrome, which can be associated with an increased risk of developing cardiovascular disease. Individuals who had college degrees had a higher prevalence of metabolic syndrome; this finding can be explained by the high rates of overweight and obesity found in subjects with college and graduate school educations.     

Differential diagnosis of Bartter syndrome,Gitelman syndrome,and pseudo–Bartter/Gitelman syndrome based on clinical characteristics

PurposePhenotypic overlap exists among type III Bartter syndrome (BS), Gitelman syndrome (GS), and pseudo-BS/GS (p-BS/GS), which are clinically difficult to distinguish. We aimed to clarify the differences between these diseases, allowing accurate diagnosis based on their clinical features.MethodsA total of 163 patients with genetically defined type III BS (n = 30), GS (n = 90), and p-BS/GS (n = 43) were included. Age at diagnosis, sex, body mass index, estimated glomerular filtration rate, and serum and urine electrolyte concentrations were determined.ResultsPatients with p-BS/GS were significantly older at diagnosis than those with type III BS and GS. Patients with p-BS/GS included a significantly higher percentage of women and had a lower body mass index and estimated glomerular filtration rate than did patients with GS. Although hypomagnesemia and hypocalciuria were predominant biochemical findings in patients with GS, 17 and 23% of patients with type III BS and p-BS/GS, respectively, also showed these abnormalities. Of patients with type III BS, GS, and p-BS/GS, 40, 12, and 63%, respectively, presented with chronic kidney disease.ConclusionsThis study clarified the clinical differences between BS, GS, and p-BS/GS for the first time, which will help clinicians establish differential diagnoses for these three conditions.     

Is the metabolic syndrome caused by a high fructose,and relatively low fat,low cholesterol diet?

The metabolic syndrome (MetS) is manifested by a lipid triad which includes elevated serum triglycerides, small LDL particles, and low high-density lipoprotein (HDL) cholesterol, by central obesity (central adiposity), insulin resistance, glucose intolerance and elevated blood pressure, and it is associated with an increased risk of type 2 diabetes and coronary heart disease. We have developed a new hypothesis regarding MetS as a consequence of a high intake in carbohydrates and food with a high glycemic index, particularly fructose, and relatively low intake of cholesterol and saturated fat. We support our arguments through animal studies which have shown that exposure of the liver to increased quantities of fructose leads to rapid stimulation of lipogenesis and accumulation of triglycerides. The adipocytes store triglycerides in lipid droplets, leading to adipocyte hypertrophy. Adipocyte hypertrophy is associated with macrophage accumulation in adipose tissue. An important modulator of obesity-associated macrophage responses in white adipose tissue is the death of adipocytes. Excess exposure to fructose intake determines the liver to metabolize high doses of fructose, producing increased levels of fructose end products, like glyceraldehyde and dihydroxyacetone phosphate, that can converge with the glycolytic pathway. Fructose also leads to increased levels of advanced glycation end products. The macrophages exposed to advanced glycation end products become dysfunctional and, on entry into the artery wall, contribute to plaque formation and thrombosis.     

Two-step TCRζ/CD3-CD4 and CD28 signaling in T cells: SH2/SH3 domains,protein-tyrosine and lipid kinases

A central question in T-cell immunity concerns the nature of intracellular signaling from the antigen receptor, the CD4/CD8 co-receptors and the CD28 antigen. Since the original discovery that T-cell receptors such as CD4 can interact with intracellular protein-tyrosine kinases such as p56^1ck, remarkable progress has been made in deciribing the signaling pathways that control T-cell growth and immune function. Here, Christopher Rudd and colleagues examine the role of protein-tyrosine kinases, SH2/SH3 domains and lipid kinases in the generation of signals from the TCRζ/CD3 complex and the CD22 antigen.     

心肌缺血病人载脂蛋白ε_2和ε_4等位基因频率增高

本研究的目的是阐明载脂蛋白(apo)E等位基因多态性和日本心肌缺血病人(IHD)之间的关系。另外检查apoE等位基因和IHD病人高脂蛋白血症(HLP)之间的相互关系。结果发现,apoE2组(apoE 3/2,E2/2,E 4/2)的频率IHD病人组与对照组相比(14。7%:7.1%)是有意义地升高,apoE 4组(apo4/3,E4,/4E4/2)频率病人组与对照组比(32。1%:21.7%)也是有意义地升高,而apoE 3/3表型频率IHD病人与对照组相比(54.1%:71.9%)是有意义降低。多数IHD病人为某一型HLP,在IHO病人中apoE2和E4携带者的HLP频率比IHD病人E3/3携带者较高,分别为87.8%,88.6%比78.0%。但这些差异在统计学上     

Salivary cortisol, APOE-ε4 allele and cognitive decline in a prospective study of older persons

Objective

We determined whether salivary cortisol levels were associated with cognitive decline at follow-up in older persons and whether this association was modified by the APOE-ε4 allele.

Methods

Within the Longitudinal Aging Study Amsterdam (LASA), a population-based prospective cohort study, 911 persons (74.5 ± 7.2 years, 46.4% male) collected salivary cortisol in the morning and late in the evening. At baseline and after 4 years of follow-up, global cognitive functioning, verbal memory performance, and processing speed were assessed. The longitudinal associations between cortisol measures and cognitive decline were estimated using linear mixed models, adjusted for potential confounders and the modifying role of the APOE-ε4 allele was examined.

Results

Lower morning cortisol levels, higher evening cortisol levels, and flattened diurnal variability of cortisol levels were associated with increased risk for memory decline in APOE-ε4 carriers but not in non-carriers.

Conclusion

Our findings suggest that in this older non-demented population APOE-ε4 carriers may be more vulnerable to the potential detrimental effect of hypothalamic-pituitary-adrenal axis dysfunction on verbal memory performance.