apoE Levels Research Articles

Exercise-induced upregulation of APOE expression is attenuated by dietary supplementation with resveratrol

The ε4 variant of the Apolipoprotein E gene (APOE4) is the most prevalent genetic risk factor for Alzheimer’s disease (AD). Approximately 25% of people carry at least one copy of the variant which increases risk of AD two-to-three-fold relative to those who carry the ε3 variant. Low ApoE levels are typically reported in Alzheimer’s patients and animal studies have reveal lower levels of ApoE in ε4 carriers relative to ε3 carriers. Therefore, reduced ApoE levels has been associated with increased risk for dementia. Physical exercise and active lifestyles are well-accepted therapeutic strategies for the prevention or delay of Alzheimer’s disease and other dementias, Additionally, there is growing evidence that the consumption of antioxidant nutritional supplements may also be therapeutic and slow progression of AD. But the effect of physical activity or antioxidant intake on APOE expression is not well-studied.The objective of this study is to determine the impact of exercise and resveratrol intake on APOE expression. We hypothesized that both resveratrol intake and exercise would increase APOE expression in brain with an additive effect when combined. Targeted replacement mice, homozygous for either APOE3 or APOE4 were randomized into four groups based on activity and resveratrol dietary supplementation: sedentary standard, sedentary resveratrol, exercise standard, and exercise resveratrol. Exercised groups were subjected to daily treadmill running for 8 weeks. Resveratrol treated groups were fed a chow supplemented with resveratrol. Results showed that exercise induced a significant increase in ApoE protein in brain cortex of both APOE3 and APOE4 mice. Resveratrol treatment alone had no significant effect on brain APOE expression, but in combination with exercise, attenuated the exercise-induced increase. While biochemical variations between APOE3 and APOE4 mice likely contribute to the differential risk for AD, the exercise-induced increase in ApoE levels in both genotypes supports a role for APOE in the therapeutic mechanisms of exercise. The timing of antioxidant supplementation in conjunction with exercise interventions should be critically considered to ensure best therapeutic efficacy of exercise. This research was supported by NIH grants R25AG047843 and 2U54MD007597-31 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Early Gestational Blood Markers to Predict Preeclampsia Complicating Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) and preeclampsia (PE) are common pregnancy complications that share some common risk factors. GDM patients are also at high risk for PE. There are no sensitive markers for prediction, especially for the occurrence of PE in GDM patients. This study investigated plasma proteins for the prediction of PE in GDM patients. A total of 10 PE, 10 GDM, and 5 PE complicated with GDM cases, as well as 10 pregnant controls without obvious complications, were included in the nested cohort. The proteomics in the plasma collected at 12-20 weeks of gestational age (GA) were analyzed by liquid chromatography‒mass spectrometry/mass spectrometry. Some potential markers, such as soluble transferrin receptor (sTfR), ceruloplasmin (CP), apolipoprotein E (ApoE) and inositol 1,4,5-trisphosphate receptor 1 (ITPR1), were validated using enzyme-linked immunosorbent assays. Functional analysis of the plasma showed that proteasome activation, pancreatic secretion, and fatty acid degradation were activated in the GDM group, and renin secretion-, lysosome-, and proteasome pathways involving iron transport and lipid metabolism were enriched in the PE group, distinguishing PE complicating GDM. Through proteomics analysis of plasma in early pregnancy, PE complicating GDM may have a unique mechanism from that of PE alone. Plasma sTfR, CP and ApoE levels have potential clinical applications in early screening.

Metabolic Disturbance of High-Saturated Fatty Acid Diet in Cognitive Preservation.

Aging continues to be the main cause of the development of Alzheimer's, although it has been described that certain chronic inflammatory pathologies can negatively influence the progress of dementia, including obesity and hyperlipidemia. In this sense, previous studies have shown a relationship between low-density lipoprotein receptor (LDLR) and the amyloid-beta (Aβ) binding activity, one of the main neuropathological features of Alzheimer's disease (AD). LDLR is involved in several processes, including lipid transport, regulation of inflammatory response and lipid metabolism. From this perspective, LDLR-/- mice are a widely accepted animal model for the study of pathologies associated with alterations in lipid metabolism, such as familial hypercholesterolemia, cardiovascular diseases, metabolic syndrome, or early cognitive decline. In this context, we induced hyperlipidemia in LDLR-/- mice after feeding with a high-saturated fatty acid diet (HFD) for 44 weeks. LDLR-/--HFD mice exhibited obesity, hypertriglyceridemia, higher glucose levels, and early hepatic steatosis. In addition, HFD increased plasmatic APOE and ubiquitin 60S levels. These proteins are related to neuronal integrity and health maintenance. In agreement, we detected mild cognitive dysfunctions in mice fed with HFD, whereas LDLR-/--HFD mice showed a more severe and evident affectation. Our data suggest central nervous system dysfunction is associated with a well-established metabolic syndrome. As a late consequence, metabolic syndrome boots many behavioral and pathological alterations recognized in dementia, supporting that the control of metabolic parameters could improve cognitive preservation and prognosis.

Effect of Total SMS Activity on LDL Catabolism in Mice.

Sphingomyelin (SM) and cholesterol are 2 key lipid partners on cell membranes and on lipoproteins. Many studies have indicated the influence of cholesterol on SM metabolism. This study examined the influence of SM biosynthesis on cholesterol metabolism. Inducible global Sms1 KO (knockout)/global Sms2 KO mice were prepared to evaluate the effect of whole-body SM biosynthesis deficiency on lipoprotein metabolism. Tissue cholesterol, SM, ceramide, and glucosylceramide levels were measured. Triglyceride production rate and LDL (low-density lipoprotein) catabolism were measured. Lipid rafts were isolated and LDL receptor mass and function were evaluated. Also, the effects of exogenous sphingolipids on hepatocytes were investigated. We found that total SMS (SM synthase) depletion significantly reduced plasma SM levels. Also, the total deficiency significantly induced plasma cholesterol, apoB (apolipoprotein B), and apoE (apolipoprotein E) levels. Importantly, total SMS deficiency, but not SMS2 deficiency, dramatically decreased LDL receptors in the liver and attenuated LDL uptake through the receptor. Further, we found that total SMS deficiency greatly reduced LDL receptors in the lipid rafts, which contained significantly lower SM and significantly higher glucosylceramide, as well as cholesterol. Furthermore, we treated primary hepatocytes and Huh7 cells (a human hepatoma cell line) with SM, ceramide, or glucosylceramide, and we found that only SM could upregulate LDL receptor levels in a dose-dependent fashion. Whole-body SM biosynthesis plays an important role in LDL cholesterol catabolism. The total SMS deficiency, but not SMS2 deficiency, reduces LDL uptake and causes LDL cholesterol accumulation in the circulation. Given the fact that serum SM level is a risk factor for cardiovascular diseases, inhibiting SMS2 but not SMS1 should be the desirable approach.

Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype

Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues – one in the hinge region and one in the C-terminal region – and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD.

Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins. The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA. We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS. This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis.

Relationship of Muscle Apolipoprotein E Expression with Markers of Cellular Stress, Metabolism, and Blood Biomarkers in Cognitively Healthy and Impaired Older Adults.

Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer's disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain. Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers. We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n = 9) or MCI (n = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max. Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age. This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.

Apolipoprotein E Gene Polymorphism Effects on Lipid Metabolism and Risk of Cerebral Infarction in Northwest Han Chinese Population.

The apolipoprotein E (ApoE) genetic variation may contribute to the development of Cerebral Infarction (CI). Serum lipid levels are known risk factors for CI, but the effect of the ApoE gene polymorphism on lipid metabolism remains unclear. This retrospective cohort study was designed to determine the role of ApoE genotypes in CI risk and the relationships between ApoE gene polymorphism and serum lipid levels among the population of northwest China. 517 CI patients and 517 non-CI controls were enrolled in the study. Polymerase chain reaction and hybridization were utilized to determine the ApoE gene polymorphisms. The ε3/ε4 genotype and ε4 allele frequency were significantly higher in CI patients than in controls. When stratified by age and sex, statistically significant differences in the distribution and frequency of the ε3/ε4 genotype and ε4 allele were found between patients and controls. Compared to ε2 carriers, ε4 carriers had significantly lower ApoE levels and higher low-density lipoprotein cholesterol (LDL-C), ApoB and ApoB/ApoA-I levels in both two groups. Additionally, control participants with ε4 carriers had significantly higher levels of lipoprotein and total cholesterol (TC) levels than ε2 carriers, while CI patients with ε4 carriers had a significantly lower level of ApoA-I. After adjusting for other established risk factors, drinking, hypertension, lipoprotein, triglycerides (TG) and ε4 allele were significant independent risk factors for CI, which was shown to be associated with a nearly two-fold CI risk. This study demonstrated that ε4 allele is independent risk factors for CI among patients in Northwest China. ApoE polymorphism was associated with CI, which was partly mediated through blood lipids and may also be mediated through non-lipid pathways. These data might be of great clinical significance in individualized preventive and therapeutic strategies.

Cerebrospinal fluid lipoproteins inhibit α-synuclein aggregation by interacting with oligomeric species in seed amplification assays

BackgroundAggregation of α-synuclein (α-syn) is a prominent feature of Parkinson’s disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification.MethodsIn this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn.ResultsWe found the high-molecular weight fraction of CSF (> 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates.ConclusionsOur results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts.

Effects of Moderate Exercise Training On ApoE And ApoCIII In Metabolic Syndrome

Introduction: Metabolic syndrome (MetS) is an endocrinopathy with a combination of cardiovascular and metabolic compounds. In our study, it is expected to obtain results showing that mortality rate, loss of workforce, and treatment costs due to disorders caused by MetS can be reduced by physical exercise. The study analyses the effect of moderate exercise training on this Apolipoprotein E (ApoE), Apolipoprotein CIII (ApoCIII), adiponectin, resistin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) which are thought to have a role in the deterioration of glucose and lipid metabolism in MetS. Methods: This clinical experimental study consists of 3 groups. The MetS+E (n=24) group, which included the participants who agreed to participate in the exercise program in addition to their medical treatment, the MetS (n=23) group who received medical treatment but did not exercise, and the Control+E (n=25) group, which included healthy volunteers who had the same protocol as MetS+E ApoE, ApoCIII, adiponectin, resistin, IL-6, and TNF-α plasma levels of all participants were measured both at the beginning of the study and at the end of the protocol. Results: At the end of the study we reached the following findings; insulin and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) levels decreased in exercise groups (p=0,03). ApoCIII levels increased in all the groups after the study (p&lt;0,01). IL-6 levels decreased in MetS+E (p&lt;0,01) and Control+E (p=0,037). ApoE (p=0,01) and TNF-α (p=0,037) levels decreased only in the Control+E group. Conclusion: Training showed metabolic, anti-inflammatory, and physical improvements independent of ApoE and ApoCIII in those with MetS.

Effect of Frozen-Thawed Embryo Transfer on the Metabolism of Children in Early Childhood.

As a routine procedure in assisted reproductive technology (ART), it is crucial to assess the safety of frozen and thawed embryo transfer (FET). We aimed to investigate the metabolic profile of children conceived through FET in their early childhood. A total of 147 children between the age of 1.5 and 4 years old, conceived through FET or naturally conceived (NC), were recruited. A total of 89 children, 65 in the FET group and 24 in the NC group (matched with the FET group based on children's BMI) were included in the final statistical analysis of biochemical markers and metabolomics. Children conceived through FET had a lower level of fasting insulin level and HORM-IR and a higher level of fasting glucose and APOE as compared to children naturally conceived. Metabolomics showed that there were 16 small differential metabolites, mainly including amino acids, carnitines, organic acids, butyric, and secondary bile acid between two groups, which enriched in Nitrogen metabolism, Butanoate metabolism, Phenylalanine metabolism, and D-Arginine and D-ornithine metabolism pathways. Although the FET group had a significantly higher level of APOE and fasting glucose, it cannot yet be considered that children in the FET group had an obvious disorder of glucose and lipid metabolism. However, the potentially more active intestinal flora and lower carnitine levels of children in the FET group suggested by metabolomics are worth further exploration.

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy

BackgroundAlzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage.MethodsWe generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity.ResultsReducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA.ConclusionIn a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.

HDL-Associated Proteins in Subjects with Polycystic Ovary Syndrome: A Proteomic Study

Serum lipoproteins, with the exception of high-density lipoprotein cholesterol (HDL-C), are increased in polycystic ovary syndrome (PCOS) and their levels may reflect the associated obesity and insulin resistance, but the nature of this association is not fully explained. Therefore, proteomic analysis of key proteins in lipoprotein metabolism was performed. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls without PCOS). Somalogic proteomic analysis was undertaken for the following 19 proteins involved in lipoprotein, and particularly HDL, metabolism: alpha-1-antichymotrypsin; alpha-1-antitrypsin; apolipoproteins A-1, B, D, E, E2, E3, E4, L1, and M; clusterin; complement C3; hemopexin; heparin cofactor II; kininogen-1; serum amyloid A-1; amyloid beta A-4; and paraoxonase-1. The levels of apolipoprotein E were higher in PCOS (p = 0.012). However, the other isoforms of ApoE, ApoE2, E3, and E4, did not differ when compared with controls. ApoM was lower in PCOS (p = 0.000002). Complement C3 was higher in PCOS (p = 0.037), as was heparin cofactor II (HCFII) (p = 0.0004). The levels of the other proteins associated with lipoprotein metabolism did not differ between PCOS and controls. These data contribute to the concern of the deleterious dyslipidemia found in PCOS, with the novel combination reported here of higher levels of ApoE, C3 and HCFII together with lower ApoM. The dysregulation of these proteins could circumvent the protective effect of HDL-C and contribute to a more atherogenic profile that may increase cardiovascular risk.

Comparative analysis between fasting and postprandial apolipoprotein B and total cholesterol/high-density lipoprotein-cholesterol ratio for atherosclerosis risk prediction in type 2 diabetes mellitus subjects of central India

Background: Type 2 diabetes mellitus (Type 2 DM), characterized by a relative insulin deficiency or insulin resistance, is associated with a cluster of metabolic abnormalities, which includes glucose intolerance, hypertension, a unique dyslipidemia, a procoagulant state, and an increase in macrovascular diseases. Aims and Objectives: The present study was conducted to correlate between fasting and postprandial apolipoprotein B and total cholesterol/high-density lipoprotein-cholesterol (TC/HDL-C) ratio for predicting the risk of atherosclerosis in T2DM subjects. Materials and Methods: Sixty clinically diagnosed cases of T2DM (age group of 35–65 years and duration of diabetes of more than 5 years) were included in the study and sixty age- and sex-matched healthy subjects were taken as the controls. In both the study groups, we measured postprandial as well as fasting lipid profile, which comprised serum TC, triglycerides (TGs), HDL-C, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B. Ratio is calculated as TC/HDL-C in both fasting and postprandial state. The statistical analysis was done using the students unpaired’-test. Results: The results of the present study showed significantly increased levels of postprandial serum TC, TGs, LDL-C, and apo B as compared to those in the fasting state (P&lt;0.05). The serum HDL-C level was significantly lower in the postprandial state as compared to that in the fasting state (P&lt;0.05). Postprandial TC/HDL-C and apo B are increased significantly as compared to fasting condition in type 2 diabetes subjects. Conclusion: The findings suggest that postprandial lipid profile, apolipoprotein B, and TC/HDL-C ratio as a cardiovascular risk factor can be utilized as simple marker utilizing simple parameters in lipid profile that significantly increased in the postprandial state.Thus, Apolipoprotein B, the marker of the number of LDL particles (for atherosclerosis) in the circulation and TC/HDL-C ratio can be routinely estimated for the atherosclerosis risk assessment in type 2 diabetes subjects in the postprandial state.

Electronegative LDL Is Associated with Plaque Vulnerability in Patients with Ischemic Stroke and Carotid Atherosclerosis

Owing to the high risk of recurrence, identifying indicators of carotid plaque vulnerability in atherothrombotic ischemic stroke is essential. In this study, we aimed to identify modified LDLs and antioxidant enzymes associated with plaque vulnerability in plasma from patients with a recent ischemic stroke and carotid atherosclerosis. Patients underwent an ultrasound, a CT-angiography, and an 18F-FDG PET. A blood sample was obtained from patients (n = 64, 57.8% with stenosis ≥50%) and healthy controls (n = 24). Compared to the controls, patients showed lower levels of total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apoB), apoA-I, apoA-II, and apoE, and higher levels of apoJ. Patients showed lower platelet-activating factor acetylhydrolase (PAF-AH) and paraoxonase-1 (PON-1) enzymatic activities in HDL, and higher plasma levels of oxidized LDL (oxLDL) and electronegative LDL (LDL(-)). The only difference between patients with stenosis ≥50% and <50% was the proportion of LDL(-). In a multivariable logistic regression analysis, the levels of LDL(-), but not of oxLDL, were independently associated with the degree of carotid stenosis (OR: 5.40, CI: 1.15-25.44, p < 0.033), the presence of hypoechoic plaque (OR: 7.52, CI: 1.26-44.83, p < 0.027), and of diffuse neovessels (OR: 10.77, CI: 1.21-95.93, p < 0.033), indicating that an increased proportion of LDL(-) is associated with vulnerable atherosclerotic plaque.

Orthodontic Compression Enhances Macrophage M2 Polarization via Histone H3 Hyperacetylation

Orthodontic tooth movement is a complex periodontal remodeling process triggered by compression that involves sterile inflammation and immune responses. Macrophages are mechanically sensitive immune cells, but their role in orthodontic tooth movement is unclear. Here, we hypothesize that orthodontic force can activate macrophages, and their activation may be associated with orthodontic root resorption. After force-loading and/or adiponectin application, the migration function of macrophages was tested via scratch assay, and Nos2, Il1b, Arg1, Il10, ApoE, and Saa3 expression levels were detected using qRT-PCR. Furthermore, H3 histone acetylation was measured using an acetylation detection kit. The specific inhibitor of H3 histone, I-BET762, was deployed to observe its effect on macrophages. In addition, cementoblasts were treated with macrophage-conditioned medium or compression force, and OPG production and cellular migration were measured. We further detected Piezo1 expression in cementoblasts via qRT-PCR and Western-blot, and its effect on the force-induced impairment of cementoblastic functions was also analyzed. Compressive force significantly inhibited macrophage migration. Nos2 was up-regulated 6 h after force-loading. Il1b, Arg1, Il10, Saa3, and ApoE increased after 24 h. Meanwhile, higher H3 histone acetylation was detected in the macrophages subjected to compression, and I-BET762 dampened the expression of M2 polarization markers (Arg1 and Il10). Lastly, even though the activated macrophage-conditioned medium showed no effect on cementoblasts, compressive force directly impaired cementoblastic function by enhancing mechanoreceptor Piezo1. Compressive force activates macrophages; specifically, it causes M2 polarization via H3 histone acetylation in the late stage. Compression-induced orthodontic root resorption is macrophage-independent, but it involves the activation of mechanoreceptor Piezo1.

Behavioral and cognitive performance of humanized APOEε3/ε3 liver mice in relation to plasma apolipoprotein E levels

Plasma apolipoprotein E levels were previously associated with the risk of developing Alzheimer’s disease (AD), levels of cerebrospinal fluid AD biomarkers, cognition and imaging brain measures. Outside the brain, the liver is the primary source of apoE and liver transplantation studies have demonstrated that liver-derived apoE does not cross the blood–brain-barrier. How hepatic apoE may be implicated in behavioral and cognitive performance is not clear. In the current study, we behaviorally tested FRGN mice with humanized liver harboring the ε3/ε3 genotype (E3-human liver (HL)) and compared their behavioral and cognitive performance with that of age-matched ε3/ε3 targeted replacement (E3-TR) mice, the latter produces human apoE3 throughout the body whereas the E3-HL mice endogenously produce human apoE3 only in the liver. We also compared the liver weights and plasma apoE levels, and assessed whether plasma apoE levels were correlated with behavioral or cognitive measures in both models. E3-HL were more active but performed cognitively worse than E3-TR mice. E3-HL mice moved more in the open field containing objects, showed higher activity levels in the Y maze, showed higher activity levels during the baseline period in the fear conditioning test than E3-TR mice, and swam faster than E3-TR mice during training to locate the visible platform in the water maze. However, E3-HL mice showed reduced spatial memory retention in the water maze and reduced fear learning and contextual and cued fear memory than E3-TR mice. Liver weights were greater in E3-HL than E3-TR mice and sex-dependent only in the latter model. Plasma apoE3 levels were similar to those found in humans and comparable in female and male E3-TR mice but higher in female E3-HL mice. Finally, we found correlations between plasma apoE levels and behavioral and cognitive measures which were predominantly model-dependent. Our study demonstrates mouse-model dependent associations between plasma apoE levels, behavior and cognition in an ‘AD-neutral’ setting and suggests that a humanized liver might be sufficient to induce mouse behavioral and cognitive phenotypes.

MicroRNA-122-5p inhibits inflammation and fibrosis in mice with acute pancreatitis by upregulating APOE level by binding to HDAC1

IntroductionThis research was designed to ascertain the mechanism of miR-122-5p in alleviating the inflammation and fibrosis of acute pancreatitis (AP) mice.Material and methodsAP mouse or cell model was established by caerulein (CAE) treatment. The coefficient of pancreas was evaluated and the expression levels of amylase (AMS) and lipase were measured by kit. The pathological changes of pancreatic tissues were observed under hematoxylin-eosin (H&amp;E) staining. The expression levels of fibrous proteins (α-SMA and Collagen Ⅰ) were detected. The expression levels of related inflammatory factors (IL-1β, IL-6, and TNF-α) were tested by ELISA. The correlations between miR-122-5p and HDAC1 or between HDAC1 and APOE were predicted and validated.ResultsIn AP mice or cells, the coefficient of pancreas was elevated (P &lt; 0.01), and the AMS expression was increased (P &lt; 0.001) while lipase expression was decreased (P &lt; 0.05). The pathological structural change was obvious and the Rongione score was elevated (P &lt; 0.001). The expression levels of α-SMA and Collagen Ⅰ were stimulated (P &lt; 0.05), and the levels of IL-1β, IL-6, and TNF-α were enhanced (P &lt; 0.001). miR-122-5p negatively regulated HDAC1 expression and HDAC1 inhibited APOE transcription. Overexpression of miR-122-5p or APOE could both reduce the inflammation and fibrosis in AP mice or cells but upregulation of HDAC1 or APOE inhibition reversed the inhibiting effect of miR-122-5p overexpression on CAE-induced inflammation and fibrosis.ConclusionsConclusively, miR-122-5p inhibited inflammation and fibrosis in an AP mouse model by the HDAC1/APOE axis.

PS-B03-13: USEFULNESS OF SEROLOGIC APE1/REF-1 AS A BIOMARKER FOR VASCULAR INFLAMMATION IN APOE DEFICIENT MICE

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is an essential multifunctional protein involved in DNA base-excision repair and in redox regulation of several functional proteins including transcription factors. However, the role of APE1/Ref-1 in atherosclerosis is unclear. we investigated the role of APE1/Ref-1 in atherosclerotic apolipoprotein E deficient (ApoE-/-) mice fed with a Western-type diet. We found that serologic APE1/Ref-1 was strongly correlated with vascular inflammation in these mice. Neutrophil/lymphocyte ratio (NLR), endothelial cell/macrophage activation, and atherosclerotic plaque formation, reflected by atherosclerotic inflammation, were increased in the ApoE-/- mice fed with a Western-type diet. APE1/Ref-1 expression was upregulated in aortic tissues of these mice, and was co-localized with cells positive for cluster of differentiation 31 (CD31) and galectin-3, suggesting endothelial cell/macrophage expression of APE1/Ref-1. Interestingly, APE1/Ref-1 plasma levels of ApoE-/- mice fed with a Western-type diet were significantly increased compared with those of the mice fed with normal diet (15.76 ± 3.19 ng/mL vs. 3.51 ± 0.50 ng/mL, p &lt; 0.05), and were suppressed by atorvastatin administration. Correlation analysis showed high correlation between plasma APE1/Ref-1 levels and NLR, a marker of systemic inflammation. The cut-off value for APE1/Ref-1 for predicting atherosclerotic inflammation at 4.903 ng/mL showed sensitivity of 100% and specificity of 91%. We conclude that APE1/Ref-1 expression is upregulated in aortic endothelial cells/macrophages of atherosclerotic mice, and that plasma APE1/Ref-1 levels could predict atherosclerotic inflammation.

Genome‐wide association study of plasma apolipoprotein E levels and risk of dementia in older adults

AbstractBackgroundThe APOE 2/3/4 polymorphism is the greatest risk factor for Alzheimer’s disease (AD). This polymorphism is also associated with variation in plasma ApoE levels and explains about 20‐25% of its genetic variance; while APOE*4 lowers, APOE*2 increases ApoE levels. Lower plasma ApoE levels have also been reported to be a risk factor of future AD and all dementia, independent of the APOE 2/3/4 polymorphism (Ann Neurol 2015;77:301). To our knowledge, no genome‐wide association study (GWAS) has been reported on plasma ApoE levels. This study was aimed to identify novel genetic factors affecting plasma ApoE levels as well as to confirm if baseline plasma ApoE levels predict future AD dementia in an older and longitudinally followed cohort of the Ginkgo Evaluation of Memory (GEM) study.MethodBaseline plasma ApoE levels were measured using an immunoturbidimetric assay in 3,031 older subjects (aged 72 to 96 years; 94.1% White). Genome‐wide genotype was performed on the available 2,737 DNA samples (96% White). Due to the small number in other ethnicities, we only included the 2,852 White subjects (2,412 cognitively normal, 440 with incident AD dementia) for plasma ApoE analysis. GWAS analysis on plasma ApoE levels was performed on 2,580 White subjects where both genotype and ApoE level data were available.ResultAs expected, the risk for AD increased from E2/2 through to E4/4 genotypes (p for trend =1.7E‐10). There was no significant difference in plasma ApoE levels between cognitively normal and AD dementia subjects (p=0.55). GWAS analysis revealed the expected associations of APOE*2 (β= 1.12; p= 3.57E‐79) and APOE*4 (β= ‐0.35; p= 2.21E‐11) with plasma ApoE levels. In addition, we observed 5 novel genome‐wide significant associations on chromosomes 1 (β= 0.921; p= 5.36E‐10), 4 (β= 0.796; p= 4.31E‐08;), 7 (β= 0.722; p= 9.64E‐09), 11 (β= 0.268; p= 2.58E‐08), and 20 (β= 1.379; p=8.25E‐09).ConclusionWe have identified multiple novel associations affecting plasma ApoE levels in addition to the established APOE association. However, we could not replicate the reported association of plasma ApoE levels with future AD, probably because of the older nature of our cohort.