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1.
APOE gene-dependent BOLD responses to a breath-hold across the adult lifespan.
Rasmussen, PM, Aamand, R, Weitzberg, E, Christiansen, M, Østergaard, L, Lund, TE
NeuroImage. Clinical. 2019;:101955
Abstract
Age and apolipoprotein E (APOE) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the APOE e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and APOE gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 APOE e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30-70 years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in APOE e4 carriers relative to non-carriers. Mid-aged (50-60 years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30-40 years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of APOE allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The APOE gene-dependent response to breath-hold may reflect NO-independent differences in vascular function.
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2.
Site-Specific Glycoprofiles of HDL-Associated ApoE are Correlated with HDL Functional Capacity and Unaffected by Short-Term Diet.
Zhu, C, Wong, M, Li, Q, Sawrey-Kubicek, L, Beals, E, Rhodes, CH, Sacchi, R, Lebrilla, CB, Zivkovic, AM
Journal of proteome research. 2019;(11):3977-3984
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Abstract
Since high-density lipoprotein (HDL) glycoprofiles are associated with HDL functional capacity, we set out to determine whether diet can alter the glycoprofiles of key HDL-associated proteins, including ApoE, a potent driver of chronic disease risk. Ten healthy subjects consumed a fast food (FF) and a Mediterranean (Med) diet for 4 days in randomized order, with a 4-day wash-out between treatments. A multiple reaction monitoring method was used to characterize the site-specific glycoprofiles of HDL proteins, and HDL functional capacity was analyzed. We describe for the first time that ApoE has 7 mucin-type O-glycosylation sites, which were not affected by short-term diet. The glycoprofiles of other HDL-associated proteins were also unaffected, except that a disialylated ApoC-III glycan was enriched after Med diet, and a nonsialylated ApoC-III glycan was enriched after FF diet. Twenty-five individual glycopeptides were significantly correlated with cholesterol efflux capacity and 21 glycopeptides were correlated with immunomodulatory capacity. Results from this study indicate that the glycoprofiles of HDL-associated proteins including ApoE are correlated with HDL functional capacity but generally unaffected by diet in the short term, except ApoC-III sialylation. These results suggest that HDL protein glycoprofiles are affected by both acute and long-term factors and may be useful for biomarker discovery.
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The Roles of Apolipoprotein E, Lipids, and Glucose in the Pathogenesis of Alzheimer's Disease.
Shinohara, M, Sato, N
Advances in experimental medicine and biology. 2019;:85-101
Abstract
Although the mechanisms by which Alzheimer's disease (AD) occurs remains unclear, it is widely accepted that both genetic and nongenetic components contribute to the pathogenesis of AD, especially the sporadic form of the disease. Nongenetic risk factors include diabetes and dyslipidemia, which are associated with impaired glucose and lipid metabolism, respectively. Apolipoprotein E (ApoE), one of the major lipid carriers in the brain, is the strongest genetic risk factor for late-onset AD. Several studies indicate that ApoE isoforms differentially affect not only lipid metabolism but also glucose metabolism or related pathways, suggesting that these risk factors contribute to the pathogenesis of AD through some common mechanisms. In this chapter, we discuss the roles of ApoE, lipids, and glucose in the pathogenesis of AD by considering their potential interactions.
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Dissociable effects of the apolipoprotein-E (APOE) gene on short- and long-term memories.
Zokaei, N, Čepukaitytė, G, Board, AG, Mackay, CE, Husain, M, Nobre, AC
Neurobiology of aging. 2019;:115-122
Abstract
Short- and long-term memory performance as a function of apolipoprotein-E (APOE) genotype was examined in older, healthy individuals using sensitive and comparable tasks to provide a more detailed description of influences of the ε4 allele (highest genetic risk factor for Alzheimer's disease) on memory. Older heterozygous and homozygous ε4 carriers and noncarriers performed 2 tasks of memory. Both tasks allowed us to measure memory for item identity and locations, using a sensitive, continuous measure of report. Long-term memory for object locations was impaired in ε4/ε4 carriers, whereas, paradoxically, this group demonstrated superior short-term memory for locations. The dissociable effects of the gene on short- and long-term memory suggest that the effect of genotype on these two types of memories, and their neural underpinnings, might not be co-extensive. Whereas the long-term memory impairment might be linked to preclinical Alzheimer's disease, the short-term memory advantage may reflect an independent, phenotypical effect of this allele on cognition.
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Dietary unsaturated fat increases HDL metabolic pathways involving apoE favorable to reverse cholesterol transport.
Morton, AM, Furtado, JD, Mendivil, CO, Sacks, FM
JCI insight. 2019;(7)
Abstract
BACKGROUND HDL that contains apolipoprotein E (apoE) is a subspecies especially active in steps in reverse cholesterol transport, a process that brings cholesterol from peripheral cells to the liver. Here, we studied the effect of dietary unsaturated fat compared with carbohydrate on the metabolism of HDL containing apoE. METHODS We enrolled 9 adults who were overweight or obese and had below-average HDL-cholesterol in a crossover study of a high-fat diet, primarily unsaturated, and a low-fat, high-carbohydrate diet. A metabolic tracer study was performed after each diet period. RESULTS Dietary fat increased the secretion, metabolism, and clearance of HDL subspecies containing apoE. Dietary fat increased the rate of clearance of large cholesterol-rich HDL containing apoE and increased their conversion to small HDL containing apoE, indicating selective cholesterol ester delivery to the liver. The high-unsaturated-fat diet did not affect the metabolism of HDL lacking apoE. CONCLUSION HDL containing apoE is a diet-responsive metabolic pathway that renders HDL more biologically active in reverse cholesterol transport. This may be a mechanism by which unsaturated fat protects against coronary heart disease. Protein-based HDL subspecies such as HDL containing apoE may be used to identify additional atheroprotective treatment targets not evident in the total HDL-cholesterol measurement. TRIAL REGISTRATION ClinicalTrials.gov NCT01399632. FUNDING NIH and the National Center for Advancing Translational Science.
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Association between Apolipoprotein E Gene Polymorphism and Alzheimer's Disease in an Iranian Population: A Meta-Analysis.
Abyadeh, M, Djafarian, K, Heydarinejad, F, Alizadeh, S, Shab-Bidar, S
Journal of molecular neuroscience : MN. 2019;(4):557-562
Abstract
The development of Alzheimer's disease (AD) has been strongly linked to the apolipoprotein E (APOE) polymorphism. A number studies have reported that the APOE ε4 allele is a genetic risk factor for developing AD, whereas the APOE ε2 and APOE ε3 alleles are considered to be neutral or even protective; however, there are conflicting data about these relationships in certain ethnic populations. Several meta-analyses have been performed to reduce the heterogeneity of results from different studies and estimate the real association in specific ethnicities. The aim of this study was to investigate the association between the APOE polymorphism and AD in an Iranian population. Our results showed a higher incidence of AD among individuals carrying the APOE ε4 allele (OR = 4.81, 95% CI: 3.28-7.05), more notably in those with the APOE ε4/e4 genotype (OR = 7.47, 95% CI: 2.35-23.73), while carrying the APOE ε3 allele was demonstrated to have a protective effect (OR = 0.40, 95% CI: 0.30-0.54). The association between the APOE ε2 allele and AD was not statically significant. However, further studies focusing on other parameters such as age, sex and environmental conditions are needed to reveal the true association between the APOE polymorphism and AD.
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OxLDL plasma levels in patients with Alzheimer's disease.
Grossi, MF, Carvalho, MDG, Silveira, JN, Gonçalves, GS, Gomes, KB, Bicalho, MA, Silva, IFO
Arquivos de neuro-psiquiatria. 2018;(4):241-246
Abstract
OBJECTIVE The objective of this study was to characterize the conventional lipid profile, oxLDL levels and ApoE polymorphism in patients with Alzheimer's disease (AD) and in elderly individuals without cognitive impairment. METHODS Eighty elderly individuals were selected and the levels of oxLDL were determined using the ELISA kit, and ApoE gene polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism. RESULTS Significantly reduced levels of oxLDL were observed in patients with AD compared to the control group. A higher frequency of the ApoE ε4 allele was observed in patients with AD compared to controls. No difference was observed for total cholesterol, HDL-C, and LDL-C levels between the two groups, while triglyceride levels were higher in controls compared with patients with AD. CONCLUSION The data analyzed together did not reveal significant differences in lipid profiles, including oxLDL levels. However, the importance of lipid changes in the genesis of the disease cannot be ruled out. Nevertheless, the ApoE ε4 allele was significantly more frequent in patients with Alzheimer's dementia in agreement with previous findings in the literature, but this genetic component did not change the levels of oxLDL.
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Antecedents of Soft Drusen, the Specific Deposits of Age-Related Macular Degeneration, in the Biology of Human Macula.
Curcio, CA
Investigative ophthalmology & visual science. 2018;(4):AMD182-AMD194
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Abstract
AMD pathobiology was irreversibly changed by the recent discovery of extracellular cholesterol-containing deposits in the subretinal space, between the photoreceptors and retinal pigment epithelium (RPE), called subretinal drusenoid deposits (SDDs). SDDs strikingly mirror the topography of rod photoreceptors in human macula, raising the question of whether an equivalent process results in a deposition related to foveal cones. Herein we propose that AMD's pathognomonic lesion-soft drusen and basal linear deposit (BLinD, same material, diffusely distributed)-is the leading candidate. Epidemiologic, clinical, and histologic data suggest that these deposits are most abundant in the central macula, under the fovea. Strong evidence presented in a companion article supports the idea that the dominant ultrastructural component is large apolipoprotein B,E-containing lipoproteins, constitutively secreted by RPE. Lipoprotein fatty acids are dominated by linoleate (implicating diet) rather than docosahexaenoate (implicating photoreceptors); we seek within the retina cellular relationships and dietary drivers to explain soft druse topography. The delivery of xanthophyll pigments to highly evolved and numerous Müller cells in the human fovea, through RPE, is one strong candidate, because Müller cells are the main reservoir of these pigments, which replenish from diet. We propose that the evolution of neuroglial relations and xanthophyll delivery that underlie exquisite human foveal vision came with a price, that is, soft drusen and sequela, long after our reproductive years.
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PCSK9: A potential regulator of apoE/apoER2 against inflammation in atherosclerosis?
Bai, XQ, Peng, J, Wang, MM, Xiao, J, Xiang, Q, Ren, Z, Wen, HY, Jiang, ZS, Tang, ZH, Liu, LS
Clinica chimica acta; international journal of clinical chemistry. 2018;:192-196
Abstract
Atherosclerosis is characterized by chronic inflammation and lipid accumulation in arterial walls, resulting in several vascular events. Proprotein convertase subtilisin kexin 9 (PCSK9), a serine protease, has a pivotal role in the degradation of hepatic low-density lipoprotein receptor (LDLR). It can increase plasma concentrations of low-density lipoprotein cholesterol and affect lipid metabolism. Recently, PCSK9 has been found to accelerate atherosclerosis via mechanisms apart from that involving the degradation of LDLR, with an emerging role in regulating the inflammatory response in atherosclerosis. Apolipoprotein E receptor 2 (apoER2), one of the LDLR family members expressed in macrophages, can bind to its ligand apolipoprotein E (apoE), exhibiting an anti-inflammatory role in atherosclerosis. Evidence suggests that apoER2 is a target of PCSK9. This review aims to discuss PCSK9 as a potential regulator of apoE/apoER2 against inflammation in atherosclerosis.
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High-density lipoprotein cholesterol, apolipoprotein E and atherogenic index of plasma are associated with risk of chronic kidney disease.
Smajić, J, Hasić, S, Rašić, S
Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina. 2018;(2):115-121
Abstract
Aim To investigate the association of parameters of lipid profile and estimated glomerular filtration rate (eGFR) p<60 ml/min/1.73m2 calculated by the Modification of Diet in Renal Disease (MDRD) in non-dialysis kidney patients. Methods The observational, case-control study enrolled patients (n=117) recruited from the Nephrological Counselling Centre of the University Clinical Centre Sarajevo and divided into two groups: group 1 eGFR (15-59 mL/min/1.73 m2 ), and group 2 (control) eGFR ≥ 60 mL/min/1.73 m2 . Concentration of lipids, lipoproteins and apolipoproteins was measured, and atherogenic index of plasma (AIP; log(TG/HDLc)) was calculated. Results High density lipoprotein cholesterol (HDLc) and apolipoprotein E (APOE) concentrations in serum were reduced [(1.02 (0.94-1.29) vs 1.15 (1.1-1.4) mmol/L; p=0.009 and 0.035 (0.026-0.04) vs 0.041 (0.034-0.05) g/L; p=0.002, respectively)], while AIP was higher in group 1 than in group 2 (0.19±0.03 vs 0.09±0.04; p=0.013). Values less than 1.09 mmol/L and 0.038 g/L for HDLc and APOE, or higher than 0.165 for AIP (p< 0.05) were associated with the eGFR below 60 ml/min/1.73 m2. The age [OR = 1.1; 95% CI (1.05-1.17)] and AIP [OR = 8.7; 95% CI (1.18- 65.0)] were independent positive predictors, while APOE was a negative predictor of eGFR reduction rate (OR=0.01; 95% CI (0.001-0.033; p<0.001). Conclusion Changes in parameters such as HDLc, APOE and AIP are associated with CKD. The study results imply the need of the AIP calculation as routine laboratory work due to its role along with the age and APOE in the prediction of renal function decline.