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1.
Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease.
Jabeen, K, Rehman, K, Akash, MSH
Journal of biochemical and molecular toxicology. 2022;(2):e22953
Abstract
Type 2 diabetes mellitus and Alzheimer's disease (AD), both are chronic and progressive diseases. Many cardiovascular and genetic risk factors are considered responsible for the development of AD and diabetes mellitus (DM). Genetic risk factor such as apolipoprotein E (APOE) plays a critical role in the progression of AD. Specifically, APOEε4 is genetically the strongest isoform associated with neuronal insulin deficiency, altered lipid homeostasis, and metabolism, decreased glucose uptake, impaired gray matter volume, and cerebrovascular functions. In this article, we have summarized the mechanisms of cardiovascular disturbances associated with AD and DM, impact of amyloid-β aggregation, and neurofibrillary tangles formation in AD. Moreover, cardiovascular risk factors leading to insulin resistance (IR) and amyloid-β aggregation are highlighted along with the effects of APOE risk alleles on cerebral, lipid, and cholesterol metabolism leading to CVD-mediated IR. Correspondingly, the contribution of IR, genetic and cardiovascular risk factors in amyloid-β aggregation, which may lead to the late onset of AD and DM, has been also discussed. In short, IR is related to significantly lower cerebral glucose metabolism, which sequentially forecasts poorer memory performance. Hence, there will be more chances for neural glucose intolerance and impairment of cognitive function in cardiac patients, particularly APOEε4 carriers having IR. Hence, this review provides a better understanding of the corresponding crosstalk among different pathways. This will help to investigate the rational application of preventive measures against IR and cognitive dysfunction, specifically in APOEε4 carriers' cardio-metabolic patients.
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Trace concentrations, heavy implications: Influences of biometals on major brain pathologies of Alzheimer's disease.
Lippi, SLP, Neely, CLC, Amaya, AL
The international journal of biochemistry & cell biology. 2022;:106136
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition that involves accumulation of toxic protein species, notably amyloid-β (Aβ)plaques and neurofibrillary tau tangles that are associated with cognitive decline. These proteins can bind metal ions, ultimately affecting their structure and function. In this review, we discuss key biometals such as zinc, copper, and iron that interact with protein species involved in AD, mainly Aβ, tau, and the late-onset AD risk factor Apolipoprotein E (APOE). These metals interact with Aβ and tau proteins, affecting their aggregation and toxicity. The allele variants of APOE also have different interactions with these metals, affecting APOE protein expression and aggregation of AD protein species.
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3.
Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β.
Chai, AB, Lam, HHJ, Kockx, M, Gelissen, IC
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(9):158980
Abstract
Since the identification of the apolipoprotein E (apoE) *ε4 allele as a major genetic risk factor for late-onset Alzheimer's disease, significant efforts have been aimed at elucidating how apoE4 expression confers greater brain amyloid-β (Aβ) burden, earlier disease onset and worse clinical outcomes compared to apoE2 and apoE3. ApoE primarily functions as a lipid carrier to regulate cholesterol metabolism in circulation as well as in the brain. However, it has also been suggested to interact with hydrophobic Aβ peptides to influence their processing in an isoform-dependent manner. Here, we review evidence from in vitro and in vivo studies extricating the effects of the three apoE isoforms, on different stages of the Aβ processing pathway including synthesis, aggregation, deposition, clearance and degradation. ApoE4 consistently correlates with impaired Aβ clearance, however data regarding Aβ synthesis and aggregation are conflicting and likely reflect inconsistencies in experimental approaches across studies. We further discuss the physical and chemical properties of apoE that may explain the inherent differences in activity between the isoforms. The lipidation status and lipid transport function of apoE are intrinsically linked with its ability to interact with Aβ. Traditionally, apoE-oriented therapeutic strategies for Alzheimer's disease have been proposed to non-specifically enhance or inhibit apoE activity. However, given the wide-ranging physiological functions of apoE in the brain and periphery, a more viable approach may be to specifically target and neutralise the pathological apoE4 isoform.
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4.
Beyond the CNS: The many peripheral roles of APOE.
Martínez-Martínez, AB, Torres-Perez, E, Devanney, N, Del Moral, R, Johnson, LA, Arbones-Mainar, JM
Neurobiology of disease. 2020;:104809
Abstract
Apolipoprotein E (APOE) is a multifunctional protein synthesized and secreted by multiple mammalian tissues. Although hepatocytes contribute about 75% of the peripheral pool, APOE can also be expressed in adipose tissue, the kidney, and the adrenal glands, among other tissues. High levels of APOE production also occur in the brain, where it is primarily synthesized by glia, and peripheral and brain APOE pools are thought to be distinct. In humans, APOE is polymorphic, with three major alleles (ε2, ε3, and ε4). These allelic forms dramatically alter APOE structure and function. Historically, the vast majority of research on APOE has centered on the important role it plays in modulating risk for cardiovascular disease and Alzheimer's disease. However, the established effects of this pleiotropic protein extend well beyond these two critical health challenges, with demonstrated roles across a wide spectrum of biological conditions, including adipose tissue function and obesity, metabolic syndrome and diabetes, fertility and longevity, and immune function. While the spectrum of biological systems in which APOE plays a role seems implausibly wide at first glance, there are some potential unifying mechanisms that could tie these seemingly disparate disorders together. In the current review, we aim to concisely summarize a wide breadth of APOE-associated pathologies and to analyze the influence of APOE in the development of several distinct disorders in order to provide insight into potential shared mechanisms implied in these various pathophysiological processes.
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5.
Impact of apolipoprotein E genetic polymorphisms on liver disease: An essential review.
Nascimento, JCR, Matos, GA, Pereira, LC, Mourão, AECCB, Sampaio, AM, Oriá, RB, Toniutto, P
Annals of hepatology. 2020;(1):24-30
Abstract
Cirrhosis is an advanced stage of liver disease, compromising liver function with systemic health implications and poor quality of life. Hepatitis C virus (HCV) infection and alcoholic liver disease are the main causes of this pathology. However, since genetic factors may play a large role in the progression and severity of liver disease, and as apolipoprotein E (apoE) has been recognised to be mainly synthesised in the liver, apoE polymorphism studies are important to better understand the causal mechanisms in liver diseases. In this review, we summarise up-to-date studies addressing how apoE polymorphisms influence liver cirrhosis and liver transplantation outcomes and potential protective mechanisms. Although more clinical studies are needed to support these findings, the apoE ɛ4 allele seems to be protective against the progression of liver cirrhosis in the majority of aetiologies and the postoperative serum apoE phenotype of the transplanted subject receptors was converted to that of the donor, indicating that >90% of apoE in plasma is synthesised in the hepatic system.
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6.
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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7.
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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8.
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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10.
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.