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1.
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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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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3.
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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Clinical Application of APOE in Alzheimer's Prevention: A Precision Medicine Approach.
Berkowitz, CL, Mosconi, L, Rahman, A, Scheyer, O, Hristov, H, Isaacson, RS
The journal of prevention of Alzheimer's disease. 2018;(4):245-252
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Abstract
Population-attributable risk models estimate that up to one-third of Alzheimer's disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.
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ApoE and Neurodegenerative Diseases in Aging.
Yin, Y, Wang, Z
Advances in experimental medicine and biology. 2018;:77-92
Abstract
Age and apolipoprotein E (ApoE) are the mightiest risk factors for dementia and cardiovascular diseases, but the underlying mechanisms remain unclear. In human, ApoE has three isoforms, ApoE2, ApoE3, and ApoE4, which are expressed by the polymorphic alleles: ɛ2, ɛ3, and ɛ4. Among the three polymorphic alleles, apoE ε4 is the most risk gene. ApoE is the main ligand for the low-density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP), functioning as the component of plasma lipoproteins in the transportation of lipids. Physiologically, ApoE is a multifunctional protein with central roles in lipid metabolism; it transports lipids, including cholesterol, through the cerebrospinal fluid (CSF) and plasma. ApoE expression regulation and apoE gene polymorphism have an important connection with neurological or neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and other diseases.
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Alzheimer's disease, apolipoprotein E and hormone replacement therapy.
Depypere, H, Vierin, A, Weyers, S, Sieben, A
Maturitas. 2016;:98-105
Abstract
Alzheimer's disease is the most frequent cause of dementia in older patients. The prevalence is higher in women than in men. This may be the result of both the higher life expectancy of women and the loss of neuroprotective estrogen after menopause. Earlier age at menopause (spontaneous or surgical) is associated with an enhanced risk of developing Alzheimer's disease. Therefore, it is postulated that estrogen could be protective against it. If so, increasing exposure to estrogen through the use of postmenopausal hormone replacement could also be protective against Alzheimer's disease. The results of the clinical studies that have examined this hypothesis are inconclusive, however. One explanation for this is that estrogen treatment is protective only if it is initiated in the years immediately after menopause. Another possibility is that the neuroprotective effects of estrogen are negated by a particular genotype of apolipoprotein E. This protein plays an important role in cholesterol transport to the neurons. Studies that have examined the link between estrogen replacement therapy, Alzheimer's disease and the E4 allele of ApoE are inconclusive. This article reviews the literature on the influence of hormone replacement therapy on the incidence and progression of Alzheimer's disease.
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Influence of APOE Gene Polymorphism on Interindividual and Interethnic Warfarin Dosage Requirement: A Systematic Review and Meta-Analysis.
Yu, WY, Sun, X, Wadelius, M, Huang, L, Peng, C, Ma, WL, Yang, GP
Cardiovascular therapeutics. 2016;(5):297-307
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Abstract
BACKGROUND Warfarin is the most extensively used coumarin anticoagulant. It has been shown that the anticoagulant effect of warfarin is associated with genetic variation. Apolipoprotein E (ApoE) is a possible candidate to influence the maintenance dose of warfarin. ApoE affects the vitamin K cycle by mediating the uptake of vitamin K into the liver. The vitamin K cycle is the drug target of warfarin. However, the association between genetic variants of the APOE gene and warfarin dose requirement is still controversial. METHODS Revman 5.3 software was used to analyze the relationship between APOE genotypes and warfarin dose requirements. RESULTS In our meta-analysis, the E2/E2 genotype was significantly associated with warfarin dose. E2/E2 patients required 12% (P = 0.0002) lower mean daily warfarin dose than E3/E3 carriers. In addition, subgroup analysis showed that Asians with the E4/E4 genotype tended to need lower warfarin maintenance doses, while the African American E4/E4 carriers needed slightly higher doses than E3/E3 carriers; however, these subgroups were very small. CONCLUSION This is the first meta-analysis of the association between APOE genotypes and warfarin dose. APOE E2/E2 might be one of the factors affecting warfarin dose requirements. The effect of APOE may vary between ethnicities.
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The role of APOE in cerebrovascular dysfunction.
Tai, LM, Thomas, R, Marottoli, FM, Koster, KP, Kanekiyo, T, Morris, AW, Bu, G
Acta neuropathologica. 2016;(5):709-23
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Abstract
The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.
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10.
[ApoE-containing HDL and the development of atherosclerosis].
Ćwiklińska, A, Strzelecki, A, Kortas-Stempak, B, Zdrojewski, Z, Wróblewska, M
Postepy higieny i medycyny doswiadczalnej (Online). 2015;:1-9
Abstract
The current state of knowledge about the role of high density lipoproteins (HDL) indicates that their anti-atherogenic function is mainly related to the effectiveness of their actions (mostly to the participation in reverse cholesterol transport from tissues to liver) rather than the concentration of HDL itself. HDLs are highly heterogeneous in their structure, lipid and protein composition and metabolic pathways and individual HDL subpopulations differ in their biological activity and effectiveness of anti-atherogenic actions. Apolipoproteins play a key role in HDL metabolism, therefore their presence in lipoproteins is one of the main criterion for HDL classification. According to this criterion HDLs containing apolipoprotein E, called HDL-apoE, are distinguished. Although the anti-atherogenic role of apo E has been demonstrated in many scientific reports, understanding of the mechanisms of formation, transformation and the role of HDL-apoE is still the aim of intense research. The results of epidemiological studies are inconclusive; some of them have demonstrated that high HDL- -apoE concentration has been associated with lower risk of developing coronary heart disease (CHD), while other studies have shown that high levels of HDL-apoE has been an independent risk factor for cardiovascular events and positively correlated with other risk factors for CHD.