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1
Begcevic Brkovic, Ilijana, Benedikt Zöhrer, Markus Scholz, Madlen Reinicke, Julia Dittrich, Surab Kamalsada, Ronny Baber, et al. "Simultaneous Mass Spectrometry-Based Apolipoprotein Profiling and Apolipoprotein E Phenotyping in Patients with ASCVD and Mild Cognitive Impairment." Nutrients 14, no. 12 (June 15, 2022): 2474. http://dx.doi.org/10.3390/nu14122474.
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Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8–12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.
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Li, Meng-Yu, Man-Ki Kwok, and Catherine Mary Schooling. "Investigating Effects of Plasma Apolipoprotein E on Ischemic Heart Disease Using Mendelian Randomization Study." Nutrients 13, no. 7 (June 28, 2021): 2215. http://dx.doi.org/10.3390/nu13072215.
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Background: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). Methods: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. Results: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. Conclusions: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.
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Hudák, Anett, Katalin Jósvay, Ildikó Domonkos, Annamária Letoha, László Szilák, and Tamás Letoha. "The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology." International Journal of Molecular Sciences 22, no. 13 (June 30, 2021): 7070. http://dx.doi.org/10.3390/ijms22137070.
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Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer’s disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (Aβ). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in Aβ pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE–heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated Aβ uptake and aggregation. ApoE2 increased the cellular internalization of monomeric Aβ, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once Aβ aggregated: while ApoE2 reduced the uptake of Aβ aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4′s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of Aβ pathology.
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Yamauchi, Kazuyoshi, and Yasushi Kawakami. "The redox status of cysteine thiol residues of apolipoprotein E impacts on its lipid interactions." Biological Chemistry 401, no. 5 (April 28, 2020): 617–27. http://dx.doi.org/10.1515/hsz-2019-0414.
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AbstractRedox-mediated modulation of cysteine (Cys) thiols has roles in various pathophysiological functions. We recently found that formation of disulfide-linked complexes of apolipoprotein (apo) E3 prevented apoE3 from irreversible oxidation. In this report, the influence of modification of Cys thiols in apoE2 and apoE3 on interactions with lipids was investigated. The apoE redox status was examined by a band-shift assay using a maleimide compound, and interactions with lipids were evaluated by a kinetic assay using dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and non-denaturing polyacrylamide gel electrophoresis. A reduction in DMPC clearance activity of apoE2 and apoE3 but not apoE4 was observed. Although hydrogen peroxide-induced oxidation decreased the clearance activity of the isoforms, apoE2 showed the greatest residual activity. Both Cys thiol masking and dimerization decreased the activity of apoE2 and apoE3 but not apoE4. In contrast, apoAII preincubation markedly increased the activity (apoE2 > apoE3 > apoE4), in accordance with the formation of apoE-AII and apoAII-E2-AII complexes. ApoAII preincubation also reduced the particle size of apoE-DMPC liposome complexes, especially for apoE2. Redox-mediated modification of Cys thiols of apoE2 or apoE3, especially disulfide bond formation with apoAII, affects lipid metabolism and consequently may be responsible for the diverse isoform specificity of apoE.
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HOFFMANN, MICHAEL M., HUBERT SCHARNAGL, ELEFTHERIA PANAGIOTOU, WERNER T. BANGHARD, HEINRICH WIELAND, and WINFRIED MÄRZ. "Diminished LDL Receptor and High Heparin Binding of Apolipoprotein E2 Sendai Associated with Lipoprotein Glomerulopathy." Journal of the American Society of Nephrology 12, no. 3 (March 2001): 524–30. http://dx.doi.org/10.1681/asn.v123524.
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Abstract. Variants of apolipoprotein E (apoE) have been linked to lipoprotein glomerulopathy, a new glomerular disease characterized by the deposition of lipoproteins in mesangial capillaries. One third of affected patients are heterozygous for apoE2 Sendai (Arg145 Pro). Variants of apoE can also produce type III hyperlipoproteinemia (HLP). Recessive type III HLP is caused by apoE2 (Arg158 Cys), a mutant with diminished low-density lipoprotein (LDL) receptor binding but halfnormal heparin binding. Dominant type III HLP is caused by mutations that markedly alter heparin binding but modestly reduce receptor binding. This study examined whether apoE2 Sendai (Arg145 Pro) was functionally different from type III HLP-producing apoE variants by expressing apoE3, apoE2 (Arg158 Cys), apoE1 (Arg146 Glu), a dominant apoE variant, and apoE2 Sendai (Arg145 Pro) in the baculovirus system. LDL receptor binding was studied using recombinant apoE complexed to phospholipid vesicles and to very lowdensity lipoprotein from a patient with familiar apoE deficiency. Compared with apoE3, receptor-binding activities of apoE2 (Arg158 Cys), apoE1 (Arg146 Glu), and apoE2 Sendai (Arg145 Pro) all were less than 5%. Heparin-binding activities were 53%, 23%, and 66%, respectively, of apoE3. The distribution of apoE2 Sendai among the major plasma lipoprotein fractions was similar to that of apoE3 and apoE2 (Arg158 Cys). ApoE2 Sendai (Arg145 Pro) represents the only known mutation within the heparin-binding domain of apoE (residues 142 through 147), revealing diminished receptor binding and almost normal heparin binding. These unique characteristics of apoE2 Sendai (Arg145 Pro) may relate to the development of lipoprotein glomerulopathy.
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Vecchio, Filomena Lo, Paola Bisceglia, Bruno Pietro Imbimbo, Madia Lozupone, Raffaela Rita Latino, Emanuela Resta, Maurizio Leone, et al. "Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease?" Therapeutic Advances in Chronic Disease 13 (January 2022): 204062232210816. http://dx.doi.org/10.1177/20406223221081605.
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Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE ( APOE) have a fourfold greater risk of developing Alzheimer’s disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction.
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Kurano, Makoto, Kazuhisa Tsukamoto, Eri Sakai, Masumi Hara, and Yutaka Yatomi. "Isoform-Dependent Effects of Apolipoprotein E on Sphingolipid Metabolism in Neural Cells." Journal of Alzheimer's Disease 85, no. 4 (February 15, 2022): 1529–44. http://dx.doi.org/10.3233/jad-215205.
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Background: Sphingosine 1-phosphate (S1P) and ceramides have been implicated in the development of Alzheimer’s disease. Apolipoprotein E (ApoE) isoforms are also involved in the development of Alzheimer’s disease. Objective: We aimed at elucidating the potential association of the ApoE isoforms with sphingolipid metabolism in the central nervous system. Methods: We investigated the modulations of apolipoprotein M (apoM), a carrier of S1P, S1P, and ceramides in Apoeshl mice, which spontaneously lack apoE, and U251 cells and SH-SY5Y cells infected with adenovirus vectors encoding for apoE2, apoE3, and apoE4. Results: In the brains of Apoeshl mice, the levels of apoM were lower, while those of ceramides were higher. In U251 cells, cellular apoM and S1P levels were the highest in the cells overexpressing apoE2 among the apoE isoforms. The cellular and medium contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 and increased in the cells overexpressing apoE4. In SH-SY5Y cells, apoM mRNA and medium S1P levels were also the highest in the cells overexpressing apoE2. The cellular contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 = apoE4 and those in medium decreased in the order of the cells overexpressing apoE3 > apoE2, while increased in the cells overexpressing apoE4. Conclusion: The modulation of apoM and S1P might partly explain the protective effects of apoE2 against Alzheimer’s disease, and the modulation of ceramides might be one of the mechanisms explaining the association of apoE4 with the development of Alzheimer’s disease.
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Chung, Won-Suk, Philip B. Verghese, Chandrani Chakraborty, Julia Joung, Bradley T. Hyman, Jason D. Ulrich, David M. Holtzman, and Ben A. Barres. "Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes." Proceedings of the National Academy of Sciences 113, no. 36 (August 24, 2016): 10186–91. http://dx.doi.org/10.1073/pnas.1609896113.
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The strongest genetic risk factor influencing susceptibility to late-onset Alzheimer’s disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by ∼12-fold whereas E2 allele is associated with an ∼twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.
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Pohlkamp, Theresa. "Apolipoprotein E: Cholesterol metabolism and Alzheimer’s pathology." Neuroforum 26, no. 1 (February 25, 2020): 25–30. http://dx.doi.org/10.1515/nf-2019-0030.
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AbstractAge is the greatest risk factor for Alzheimer’s disease (AD). Today, due to an increase in global life expectancy, AD-related deaths are ranked as the sixth most common cause of death. The allele isoform ɛ4 of apolipoprotein E (ApoE4) is the most important genetic risk factor for AD. Three ApoE isoforms are common in humans: ApoE2, ApoE3, and ApoE4. ApoE3 is the most frequent isoform and considered neutral with regards to AD, whereas the isoform ApoE2 is protective. Thus it is important to understand how ApoE isoforms affect amyloid-β (Aβ) and tau toxicity, the key drivers of AD pathology. Aβ and tau accumulate to form the hallmarks of AD, plaques and neurofibrillary tangles, respectively. ApoE, primarily expressed by astrocytes, is the major lipid transporter in the brain. In this review I summarize some important historic and scientific aspects of our progress in understanding the role of the cholesterol transporter ApoE in the brain, and how the isoform ApoE4 contributes to AD pathology.
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Iannucci, Jaclyn, Abhik Sen, and Paula Grammas. "Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro." Current Issues in Molecular Biology 43, no. 1 (May 27, 2021): 215–25. http://dx.doi.org/10.3390/cimb43010018.
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Mutations to the cholesterol transport protein apolipoprotein E (ApoE) have been identified as a major risk factor for the development of sporadic or late-onset Alzheimer’s disease (AD), with the e4 allele representing an increased risk and the rare e2 allele having a reduced risk compared to the primary e3 form. The reasons behind the change in risk are not entirely understood, though ApoE4 has been connected to inflammation and toxicity in both the brain and the periphery. The goal of this study was to better understand how the ApoE isoforms (ApoE2/3/4) confer differential AD-related risk by assessing cell-specific ApoE-related neuroinflammatory and neurotoxic effects. We compared the effects of ApoE isoforms in vitro on human astrocytes, a human immortalized microglia cell line (HMC3), and the human neuroblastoma cell line SH-SY5Y. Cells were treated for 24 h with or without recombinant ApoE2, ApoE3, or ApoE4 (20 nM) and inflammation and toxicity markers assessed. Our results indicated the expression of inflammatory cytokines IL-1β, TNFα, and IL-6 in human astrocytes was increased in response to all ApoE isoforms, with ApoE4 evoking the highest level of cytokine expression. In response to ApoE2 or ApoE3, microglial cells showed reduced levels of microglial activation markers TREM2 and Clec7a, while ApoE4 induced increased levels of both markers. ApoE2 promoted neuron survival through increased BDNF release from astrocytes. In addition, ApoE2 promoted, while ApoE4 reduced, neuronal viability. Overall, these results suggest that ApoE4 acts on cells in the brain to promote inflammation and neuronal injury and that the deleterious effects of ApoE4 on these cells may, in part, contribute to its role as a risk factor for AD.
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Civeira-Marín, María, Ana Cenarro, Victoria Marco-Benedí, Ana M. Bea, Rocío Mateo-Gallego, Belén Moreno-Franco, José M. Ordovás, Martín Laclaustra, Fernando Civeira, and Itziar Lamiquiz-Moneo. "APOE Genotypes Modulate Inflammation Independently of Their Effect on Lipid Metabolism." International Journal of Molecular Sciences 23, no. 21 (October 26, 2022): 12947. http://dx.doi.org/10.3390/ijms232112947.
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The association between APOE genotypes and cardiovascular disease (CVD) is partially mediated by LDL-cholesterol concentration but persists after adjusting for lipid levels and other cardiovascular risk factors. Data from the Aragon Workers Health Study (AWHS) (n = 4159) and the Lipid Unit at the Hospital Universitario Miguel Servet (HUMS) (n = 3705) were used to investigate the relationship between C-reactive protein (CRP) levels and APOE genotype. Lipoprotein particle and GlycA concentrations were analyzed in a subsample from AWHS. APOE genotyping was carried out by the Sanger method in both cohorts. APOE4 carriers had significantly lower levels of CRP than APOE3 carriers. Furthermore, APOE4 carriers had cholesterol-enriched LDL particles compared to APOE2 carriers. APOE4 carriers also had higher concentrations of small, medium, and large LDL particles. CRP levels were not associated with lipoprotein particle number, size, or composition. GlycA levels were not associated with APOE genotypes. However, GlycA levels were significantly associated with the size and the amount of cholesterol contained in HDL, VLDL, and LDL particles. APOE genotype influences CRP concentration regardless of lipid profile. APOE2 carriers showed the highest CRP levels, followed by APOE3 and APOE4. A more atherogenic lipid profile, but not inflammatory markers could partly explain the higher CVD risk observed in APOE4 carriers.
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Santos-Ferreira, Cátia, Rui Baptista, Manuel Oliveira-Santos, Regina Costa, José Pereira Moura, and Lino Gonçalves. "Apolipoprotein E2 Genotype Is Associated with a 2-Fold Increase in the Incidence of Type 2 Diabetes Mellitus: Results from a Long-Term Observational Study." Journal of Lipids 2019 (August 7, 2019): 1–8. http://dx.doi.org/10.1155/2019/1698610.
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Background. The apolipoprotein E (APOE) polymorphisms are associated with cardiovascular (CV) disease, but its interaction with type 2 diabetes mellitus (T2DM) long-term incidence is unknown. We investigated the association between APOE genotype and long-term (i) CV events and (ii) T2DM incidence in a Southern European primary prevention cohort. Methods. We assessed individual APOE genotypes in a total of 436 patients followed at a lipid clinic, with a 15-year median follow-up time. We collected data on major CV events (CV death, myocardial infarction, and stroke) and T2DM development. Results. No differences were found regarding major CV event incidence among the different APOE genotypes. However, after excluding 39 patients with a prior history of T2DM, APOE2 carriers displayed a higher incidence of T2DM during follow-up (42.2%) than APOE3 (27.1%) and APOE4 (28.7%) carriers. The age-, sex-, triglycerides-, and statin usage-adjusted OR for T2DM incidence in APOE2 carriers was 1.8 (95%CI 1.1-2.9, p=0.03), compared with wild-type APOE3. To address the role of statins as a confounder, we analyzed T2DM incidence in statin-treated patients. Statin-treated APOE2 carriers also had a higher T2DM incidence (57.9%), in comparison with APOE3 homozygotes (31.6%) and APOE4 carriers (32.5%). After adjustment for confounding, APOE2 carriers on statins displayed a similar twofold increase in T2DM risk compared to APOE3 homozygotes (OR 2.1, 95%CI 1.1-4.0, p=0.03). Conclusion. Our findings suggest a twofold increase in T2DM incidence in APOE2 carriers. This may prompt for a specific glucose dysmetabolism follow-up that might be tailored on the APOE genotype.
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Villeneuve, Sylvia, Diane Brisson, and Daniel Gaudet. "Influence of Abdominal Obesity on the Lipid-Lipoprotein Profile in Apoprotein E2/4 Carriers: The Effect of an Apparent Duality." Journal of Lipids 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/742408.
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Background. Apolipoprotein (Apo) E plays a key role in the handling of lipoprotein particles with ApoE2 and ApoE4 frequently having opposite effects compared to ApoE3. Some individuals simultaneously carry both E2 and E4 alleles. The impact of the ApoE2/4 genotype on lipid concentrations and its consequences on health remain poorly documented.Objective. This study compared the lipid profile between ApoE2/4 carriers and other ApoE genotypes in relation to the waist circumference.Methods. Cholesterol, triglyceride (TG), and ApoB concentrations were measured among 2,680 Caucasians. Multivariate logistic regression models were used to estimate the contribution of ApoE2/4 to various dyslipidemic profiles associated with abdominal obesity.Results. In presence of abdominal obesity, the lipid profile was as deteriorated in ApoE2/4 carriers as in carriers of other ApoE genotypes. There was a more pronounced effect on TG-rich lipoproteins, particularly in ApoE2/2 (a feature of type III dysbetalipoproteinemia), and non-high-density lipoprotein (HDL) cholesterol in ApoE4/4. Compared to ApoE2/2, ApoE2/4 carriers presented lower very-low-density lipoprotein (VLDL) cholesterol concentrations and VLDL-cholesterol/TG ratios, with or without obesity, and higher low-density lipoprotein (LDL) cholesterol concentrations.Conclusion. In presence of abdominal obesity, the influence of the ApoE2 allele could be less pronounced than that of ApoE4 among ApoE2/4 individuals.
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Alata, Wael, Yue Ye, Isabelle St-Amour, Milène Vandal, and Frédéric Calon. "Human Apolipoprotein E ε4 Expression Impairs Cerebral Vascularization and Blood—Brain Barrier Function in Mice." Journal of Cerebral Blood Flow & Metabolism 35, no. 1 (October 22, 2014): 86–94. http://dx.doi.org/10.1038/jcbfm.2014.172.
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Human apolipoprotein E ( APOE) exists in three isoforms ε2, ε3, and ε4, of which APOE4 is the main genetic risk factor of Alzheimer's disease (AD). As cerebrovascular defects are associated with AD, we tested whether APOE genotype has an impact on the integrity and function of the blood—brain barrier (BBB) in human APOE-targeted replacement mice. Using the quantitative in situ brain perfusion technique, we first found lower (13.0% and 17.0%) brain transport coefficient (Clup) of [3H]-diazepam in APOE4 mice at 4 and 12 months, compared with APOE2 and APOE3 mice, reflecting a decrease in cerebral vascularization. Accordingly, results from immunohistofluorescence experiments revealed a structurally reduced cerebral vascularization (26% and 38%) and thinner basement membranes (30% and 35%) in 12-month-old APOE4 mice compared with APOE2 and APOE3 mice, suggesting vascular atrophy. In addition, APOE4 mice displayed a 29% reduction in [3H]-d-glucose transport through the BBB compared with APOE2 mice without significant changes in the expression of its transporter GLUT1 in brain capillaries. However, an increase of 41.3% of receptor for advanced glycation end products (RAGE) was found in brain capillaries of 12-month-old APOE4 mice. In conclusion, profound divergences were observed between APOE genotypes at the cerebrovascular interface, suggesting that APOE4-induced BBB anomalies may contribute to AD development.
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Cambruzzi, Eduardo, and Karla Lais Pêgas. "Pathogenesis, histopathologic findings and treatment modalities of lipoprotein glomerulopathy: A review." Brazilian Journal of Nephrology 41, no. 3 (September 2019): 393–99. http://dx.doi.org/10.1590/2175-8239-jbn-2018-0148.
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Abstract Lipoprotein glomerulopathy (LPG) is an uncommon cause of nephrotic syndrome and/or kidney failure. At microscopy, LPG is characterized by the presence of lipoprotein thrombi in dilated glomerular capillaries due to different ApoE mutations. ApoE gene is located on chromosome 19q13.2, and can be identified in almost all serum lipoproteins. ApoE works as a protective factor in atherosclerosis due its interaction with receptor-mediated lipoprotein clearance and cholesterol receptor. Most common polymorphisms include ApoE2/2, ApoE3/2, ApoE3/3, ApoE4/2, ApoE4/3, and ApoE4/4. All age-groups can be affected by LPG, with a discrete male predominance. Compromised patients typically reveal dyslipidemia, type III hyperlipoproteinemia, and proteinuria. LPG treatment includes fenofibrate, antilipidemic drugs, steroids, LDL aphaeresis, plasma exchange, antiplatelet drugs, anticoagulants, urokinase, and renal transplantation. Recurrence in kidney graft suggests a pathogenic component(s) of extraglomerular humoral complex resulting from abnormal lipoprotein metabolism and presumably associated to ApoE.
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Gao, Huiling, Wei Zheng, Cheng Li, and He Xu. "Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons." International Journal of Molecular Sciences 22, no. 21 (October 27, 2021): 11582. http://dx.doi.org/10.3390/ijms222111582.
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Hydrogen peroxide (H2O2)-induced neuronal apoptosis is critical to the pathology of Alzheimer’s disease (AD) as well as other neurodegenerative diseases. The neuroprotective effects of apolipoprotein (ApoE) isoforms against apoptosis and the underlying mechanism remains controversial. Here, we have generated human cortical neurons from iPSCs and induced apoptosis with H2O2. We show that ApoE2 and ApoE3 pretreatments significantly attenuate neuronal apoptosis, whereas ApoE4 has no neuroprotective effect and higher concentrations of ApoE4 even display toxic effect. We further identify that ApoE2 and ApoE3 regulate Akt/FoxO3a/Bim signaling pathway in the presence of H2O2. We propose that ApoE alleviates H2O2-induced apoptosis in human iPSC-derived neuronal culture in an isoform specific manner. Our results provide an alternative mechanistic explanation on how ApoE isoforms influence the risk of AD onset as well as a promising therapeutic target for diseases involving neuronal apoptosis in the central nervous system.
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Zhang, Ting, Pengyuan Dai, Dong Cheng, Liang Zhang, Zijiang Chen, Xiaoqian Meng, Fumiao Zhang, et al. "Obesity occurring in apolipoprotein E-knockout mice has mild effects on fertility." REPRODUCTION 147, no. 2 (February 2014): 141–51. http://dx.doi.org/10.1530/rep-13-0470.
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The Apolipoprotein (Apo) family is implicated in lipid metabolism. There are five types of Apo: Apoa, Apob, Apoc, Apod, and Apoe. Apoe has been demonstrated to play a central role in lipoprotein metabolism and to be essential for efficient receptor-mediated plasma clearance of chylomicron remnants and VLDL remnant particles by the liver. Apoe-deficient (Apoe−/−) mice develop atherosclerotic plaques spontaneously, followed by obesity. In this study, we investigated whether lipid deposition caused by Apoe knockout affects reproduction in female mice. The results demonstrated that Apoe−/− mice were severely hypercholesterolemic, with their cholesterol metabolism disordered, and lipid accumulating in the ovaries causing the ovaries to be heavier compared with the WT counterparts. In addition, estrogen and progesterone decreased significantly at D 100. Quantitative PCR analysis demonstrated that at D 100 the expression of cytochromeP450 aromatase (Cyp19a1), 3β-hydroxysteroid dehydrogenase (Hsd3b), mechanistic target of rapamycin (Mtor), and nuclear factor-κB (Nfkb) decreased significantly, while that of BCL2-associated agonist of cell death (Bad) and tuberous sclerosis complex 2 (Tsc2) increased significantly in the Apoe−/− mice. However, there was no difference in the fertility rates of the Apoe−/− and WT mice; that is, obesity induced by Apoe knockout has no significant effect on reproduction. However, the deletion of Apoe increased the number of ovarian follicles and the ratio of ovarian follicle atresia and apoptosis. We believe that this work will augment our understanding of the role of Apoe in reproduction.
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Kraft, Lucas, Louise Serpell, and John Atack. "A Biophysical Approach to the Identification of Novel ApoE Chemical Probes." Biomolecules 9, no. 2 (January 29, 2019): 48. http://dx.doi.org/10.3390/biom9020048.
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Alzheimer’s disease (AD) is the most common type of dementia and, after age, the greatest risk factor for developing AD is the allelic variation of apolipoprotein E (ApoE), with homozygote carriers of the ApoE4 allele having an up to 12-fold greater risk of developing AD than noncarriers. Apolipoprotein E exists as three isoforms that differ in only two amino acid sites, ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158), and ApoE4 (Arg112/Arg158). These amino acid substitutions are assumed to alter ApoE structure and function, and be responsible for the detrimental effects of ApoE4 via a mechanism that remains unclear. The hypothesis that a structural difference between ApoE4 and ApoE3 (and ApoE2) is the cause of the ApoE4-associated increased risk for AD forms the basis of a therapeutic approach to modulate ApoE4 structure, and we were therefore interested in screening to identify new chemical probes for ApoE4. In this regard, a high-yield protocol was developed for the expression and purification of recombinant full-length ApoE, and three diverse biophysical screening assays were established and characterized; an optical label-free assay (Corning Epic) for hit identification and microscale thermophoresis (MST) and isothermal titration calorimetry (ITC) as orthogonal assays for hit confirmation. The 707 compounds in the National Institute of Health clinical collection were screened for binding to ApoE4, from which six confirmed hits, as well as one analogue, were identified. Although the compounds did not differentiate between ApoE isoforms, these data nevertheless demonstrate the feasibility of using a biophysical approach to identifying compounds that bind to ApoE and that, with further optimization, might differentiate between isoforms to produce a molecule that selectively alters the function of ApoE4.
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Herrmann, Wolfgang, Sigrid Hanf, Jürgen Reißner, Hans Kaffarnik, Sabine Motzny, and Armin Steinmetz. "The Influence of Apolipoprotein E Polymorphism on Plasma Concentrations of Apolipoprotein B and A-I During the First Year of Life." Pediatrics 93, no. 2 (February 1, 1994): 296–302. http://dx.doi.org/10.1542/peds.93.2.296.
Full textAbstract:
Apolipoprotein (apo)E polymorphism has been shown to be associated with different serum levels of cholesterol, apoB, and apoE. In clarifying the degree of influence of the apoE isoforms, investigations in an early stage of life are useful. The aim of the study was to investigate the plasma levels of apoB and apoA-I as structural proteins of low and high density lipoproteins, in relation to apoE phenotypes during the first year of life. Conclusions about the relationship between apoE phenotype and the development of the lipoprotein patterns can be drawn. The concentrations of apoB and apoA-I in capillary plasma as well as the apoE phenotype were estimated in 199 newborns (7 days old) and in follow-up investigations of a subgroup of 45 at 1, 4, 12, 24, and 52 weeks. The phenotype frequencies were as follows: 70% apoE 3/3, 16% apoE 3/4, 10% apoE 2/3, 2.5% apoE 2/2, and 1.5% apoE 4/2. The plasma concentrations of apoB and apoA-I in the newborns (7 days old) averaged 55% of the adult value and increased toward the end of the first year of life up to approximately 85%. The course of the plasma concentrations of apoB and apoA-I in relation to the apoE phenotype showed that, beginning at 24 weeks, the apoB levels were significantly lower for the phenotype E 2/2 and in tendency also for the phenotype E 2/3 in comparison with E 3/3. At the end of the first year of life, the apoB levels in infants with apoE phenotype 2/2 increased only by 50% and yielded 0.59 g/L. But the apoB levels of infants with other apoE phenotypes (apoE 2/3, 3/3, 4/2, 4/3) increased during the same period related to their phenotype between 78% ad 90% (absolute 0.71 to 0.91 g/L). In contrast, apoA-I concentrations were independent of the apoE phenotype. It is concluded that already in infancy apoE polymorphism influences the metabolism of apoB- and apoE-containing lipoproteins.
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Gunzburg, Menachem J., Matthew A. Perugini, and Geoffrey J. Howlett. "Structural Basis for the Recognition and Cross-linking of Amyloid Fibrils by Human Apolipoprotein E." Journal of Biological Chemistry 282, no. 49 (October 4, 2007): 35831–41. http://dx.doi.org/10.1074/jbc.m706425200.
Full textAbstract:
Apolipoprotein (apo) E is a well characterized lipid-binding protein in plasma that also exists as a common nonfibrillar component of both cerebral and systemic amyloid deposits. A genetic link between a common isoform of apoE, apoE4, and the incidence of late onset Alzheimer disease has drawn considerable attention to the potential roles of apoE in amyloid-related disease. We examined the interactions of apoE with amyloid fibrils composed of apoC-II and the amyloid-β (Aβ) peptide. Aggregates of apoE with Aβ and apoC-II are found in Alzheimer and atherosclerotic plaques, respectively. Sedimentation velocity and fibril size distribution analysis showed that apoE3 and E4 isoforms bind and noncovalently cross-link apoC-II fibrils in a similar manner. This ability to cross-link apoC-II fibrils was abolished by the dissociation of the apoE tetramer to monomers or by thrombin cleavage to yield separate N- and C-terminal domains. Preparative ultracentrifuge binding studies indicated that apoE and the isolated N- and C-terminal domains of apoE bind with submicromolar affinities to both apoC-II and Aβ fibrils. Fluorescence quenching and resonance energy transfer experiments confirmed that both domains of apoE interact with apoC-II fibrils and demonstrated that the binding of the isolated N-terminal domain of apoE to apoC-II or Aβ fibrils is accompanied by a significant conformational change with helix three of the domain moving relative to helix one. We propose a model involving the interaction of apoE with patterns of aligned residues that could explain the general ability of apoE to bind to a diverse range of amyloid fibrils.
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Mamun, Abdullah Al, Md Sahab Uddin, Md Fahim Bin Bashar, Sonia Zaman, Yesmin Begum, Israt Jahan Bulbul, Md Siddiqul Islam, et al. "Molecular Insight into the Therapeutic Promise of Targeting APOE4 for Alzheimer’s Disease." Oxidative Medicine and Cellular Longevity 2020 (May 15, 2020): 1–16. http://dx.doi.org/10.1155/2020/5086250.
Full textAbstract:
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes chronic cognitive dysfunction. Most of the AD cases are late onset, and the apolipoprotein E (APOE) isoform is a key genetic risk factor. The APOE gene has 3 key alleles in humans including APOE2, APOE3, and APOE4. Among them, APOE4 is the most potent genetic risk factor for late-onset AD (LOAD), while APOE2 has a defensive effect. Research data suggest that APOE4 leads to the pathogenesis of AD through various processes such as accelerated beta-amyloid aggregations that raised neurofibrillary tangle formation, cerebrovascular diseases, aggravated neuroinflammation, and synaptic loss. However, the precise mode of actions regarding in what way APOE4 leads to AD pathology remains unclear. Since APOE contributes to several pathological pathways of AD, targeting APOE4 might serve as a promising strategy for the development of novel drugs to combat AD. In this review, we focus on the recent studies about APOE4-targeted therapeutic strategies that have been advanced in animal models and are being prepared for use in humans for the management of AD.
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Sheng, Huaxin, Daniel T. Laskowitz, Ellen Bennett, Donald E. Schmechel, Robert D. Bart, Ann M. Saunders, Robert D. Pearlstein, Allen D. Roses, and David S. Warner. "Apolipoprotein E Isoform-Specific Differences in Outcome from Focal Ischemia in Transgenic Mice." Journal of Cerebral Blood Flow & Metabolism 18, no. 4 (April 1998): 361–66. http://dx.doi.org/10.1097/00004647-199804000-00003.
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Apolipoprotein E (apoE), a 34-kD glycosylated lipid-binding protein, is expressed as three common isoforms in humans (E2, E3, or E4). Clinical evidence suggests that the apoE genotype (APOE) may be a risk factor for poor outcome after acute central nervous system injury. This was examined further in transgenic mice constructed with the human APOE3 or APOE4 gene under the control of human promoter and tissue expression elements. Presence of human apoE3 and apoE4 proteins in brains of human APOE homozygous transgenic mice was confirmed by Western blotting. APOE3 (n = 12) and APOE4 (n = 10) mice underwent 60 minutes of middle cerebral artery occlusion. After 24-hour recovery, infarct size was measured. Infarct volumes (mean ± standard deviation) were smaller in the APOE3 group (cortex: APOE3 = 18 ± 4 mm3; APOE4 = 30 ± 11 mm3, P = 0.04; subcortex: APOE3 = 12 ± 4 mm3; APOE4 = 18 ± 4 mm3, P = 0.003). Hemiparesis was less severe in APOE3 mice ( P = 0.02). These data indicate that human isoform-specific effects of apoE are relevant to acute pathomechanisms of focal ischemic brain damage when examined in the mouse. APOE transgenic mice may provide an appropriate model to examine the mechanistic basis for the differential effects of human apoE isoforms in acute central nervous system injury.
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Hsu, Michelle, Mehek Dedhia, Wim Crusio, and Anna Delprato. "Sex differences in gene expression patterns associated with the APOE4 allele." F1000Research 8 (April 5, 2019): 387. http://dx.doi.org/10.12688/f1000research.18671.1.
Full textAbstract:
Background: The APOE gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the APOE gene: APOE2, APOE3, and APOE4. The APOE4 allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. Methods: In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the APOE4 allele in order to identify possible sex-related differences that may be relevant to AD. Results: Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of APOE in APOE4-positive individuals. The number of these genes was much higher in APOE4-positive females than in APOE4-positive males, who in turn had more of such genes than APOE4-negative control groups. Conclusions: Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of APOE with respect to sex differences and AD.
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Zhao, Na, Olivia N. Attrebi, Yingxue Ren, Wenhui Qiao, Berkiye Sonustun, Yuka A. Martens, Axel D. Meneses, et al. "APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid." Science Translational Medicine 12, no. 529 (February 5, 2020): eaay1809. http://dx.doi.org/10.1126/scitranslmed.aay1809.
Full textAbstract:
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.
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Marin, Guilherme B., Marli H. Tavella, João F. Guerreiro, Sidney E. B. Santos, and Marco A. Zago. "Absence of the E2 allele of apolipoprotein in Amerindians." Brazilian Journal of Genetics 20, no. 4 (December 1997): 741–43. http://dx.doi.org/10.1590/s0100-84551997000400029.
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Determination of the ApoE allele distribution in five South American Amerindian tribes revealed absence of the ApoE2 allele, accompanied by high ApoE3 and low ApoE4 allele frequencies for most tribes, a distribution only previously reported for the Inuit Eskimo from Greenland.
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Zhang, Xin, Long Wu, Russell H. Swerdlow, and Liqin Zhao. "Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease." Cells 12, no. 3 (January 25, 2023): 410. http://dx.doi.org/10.3390/cells12030410.
Full textAbstract:
Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer’s disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD.
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Dunk, Michelle M., and Ira Driscoll. "Total Cholesterol and APOE-Related Risk for Alzheimer’s Disease in the Alzheimer’s Disease Neuroimaging Initiative." Journal of Alzheimer's Disease 85, no. 4 (February 15, 2022): 1519–28. http://dx.doi.org/10.3233/jad-215091.
Full textAbstract:
Background: APOE ɛ4 allele confers greatest genetic risk for Alzheimer’s disease (AD), yet mechanisms underlying this risk remain elusive. APOE is involved in lipid metabolism, and literature suggest relationships between high total cholesterol, APOE, and AD. Further investigation is needed to elucidate the potential role of total cholesterol in AD risk. Objective: To investigate the relationship between total cholesterol and APOE-related AD risk in the Alzheimer’s Disease Neuroimaging Initiative. Methods: Participants (N = 1,534) were classified as controls (cognitively normal; N = 404), early mild cognitive impairment (MCI; N = 294), late MCI (N = 539), or AD (N = 297). Total cholesterol levels were compared across APOE genotype and diagnosis. Mendelian randomization was performed to examine causality between total cholesterol and AD risk using APOE as a genetic instrument. Results: Total cholesterol was higher in APOE4+ compared to APOE3 and APOE2+ (ps < 0.04) carriers. Those with AD and late MCI (ps < 0.001) had higher total cholesterol than the control group. Comparing APOE4+ to APOE3 carriers, the predicted odds ratios per mg/dL greater total cholesterol were 1.11 for MCI (95% confidence interval, 1.04–7.32), 1.05 for early MCI (1.01–3.22), 1.13 for late MCI (1.05–11.70), 1.21 for AD (1.09–54.05), and 1.13 for composite dementia (MCI or AD; 1.06–11.59) (ps < 0.05, F-statistics > 10). Conclusion: Higher total cholesterol may be a significant contributor to AD risk, particularly in APOE4 carriers who, based on existing literature, tend to have impaired cholesterol metabolism. Our findings highlight a possible mechanism by which APOE confers AD risk and indicate potential for AD risk modification through maintenance of healthy total cholesterol levels.
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Ozen, Ezgi, Rada G. Mihaylova, Natalie J. Lord, Julie A. Lovegrove, and Kim G. Jackson. "Association between APOE Genotype with Body Composition and Cardiovascular Disease Risk Markers Is Modulated by BMI in Healthy Adults: Findings from the BODYCON Study." International Journal of Molecular Sciences 23, no. 17 (August 29, 2022): 9766. http://dx.doi.org/10.3390/ijms23179766.
Full textAbstract:
Body mass index (BMI) has been suggested to play an important role in the relationship between the APOLIPOPROTEIN (APO)E genotype and cardiovascular disease (CVD) risk. Using data from the BODYCON cross-sectional study (n = 360 adults) we assessed the association between body composition and CVD risk markers according to APOE genotype, with examination of the role of BMI. In this study cohort, the APOE2/E3 group had lower fasting blood lipids than APOE4 carriers and APOE3/E3 group (p ≤ 0.01). After stratifying the group according to BMI, APOE4 carriers in the normal BMI subgroup had a higher lean mass compared with the APOE3/E3 group (p = 0.02) whereas in the overweight/obese subgroup, the android to gynoid percentage fat ratio was lower in APOE4 carriers than APOE3/E3 group (p = 0.04). Fasting lipid concentrations were only different between the APOE2/E3 and other genotype groups within the normal weight BMI subgroup (p ≤ 0.04). This finding was associated with a lower dietary fibre and a higher trans-fat intake compared with APOE4 carriers, and a lower carbohydrate intake relative to the APOE3/E3 group. Our results confirm previous reports that BMI modulates the effect of APOE on CVD risk markers and suggest novel interactions on body composition, with diet a potential modulator of this relationship.
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Richard, Pascale, Isabelle Beucler, Maria Pascual De Zulueta, Nicolas Biteau, Jean-Luc De Gennes, and Albert Iron. "Compound Heterozygote for Both Rare Apolipoprotein E1(Gly127→Asp, Arg158→Cys) and E3(Cys112 → Arg, Arg251 → Gly) Alleles in a Multigeneration Pedigree with Hyperlipoproteinaemia." Clinical Science 93, no. 1 (July 1, 1997): 89–95. http://dx.doi.org/10.1042/cs0930089.
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1. A French multigeneration pedigree with hyperlipoproteinaemia was investigated for the transmission of the rare apolipoprotein E1(Gly127 → Asp, Arg158 → Cys) variant. The proband, a 46-year-old male carrying the rare apoE1 variant, presented a severe type III hyperlipoproteinaemia like his three brothers and his sister. 2. ApoE phenotyping and genotyping showed a discrepancy in the second allele carried by the proband's wife and two of her children, thus suggesting another apoE gene mutation. Cloning and sequencing of the entire exon 4 demonstrated a point mutation at codon 251, leading to an apoE3(Cys112 → Arg, Arg251 → Gly) allele. The proband's wife was normolipaemic and heterozygous for this rare isoform and the common apoE3 protein. The rare apoE3(Cys112 → Arg, Arg251 → Gly) allele has been transmitted to her two daughters. The first, aged 19, was normolipaemic and heterozygous for this allele and the common apoE2 allele. The second, carrying both the rare isoforms apoE1(Gly127 → Asp, Arg158 → Cys) and apoE3(Cys112 → Arg, Arg251 → Gly), presented a hypertriglyceridaemia at the age of 10. 3. The exploration of apoE status associated with plasma lipid levels and lipoprotein profiles in this three-generation pedigree made it possible to describe a compound heterozygote for two mutated alleles, one mutation being located in the N-terminal domain of the apoE protein and the other arising in the C-terminal domain.
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Simon, Romain, Marion Girod, Catherine Fonbonne, Arnaud Salvador, Yohann Clément, Pierre Lantéri, Philippe Amouyel, Jean Charles Lambert, and Jérôme Lemoine. "Total ApoE and ApoE4 Isoform Assays in an Alzheimer's Disease Case-control Study by Targeted Mass Spectrometry (n = 669): A Pilot Assay for Methionine-containing Proteotypic Peptides." Molecular & Cellular Proteomics 11, no. 11 (August 23, 2012): 1389–403. http://dx.doi.org/10.1074/mcp.m112.018861.
Full textAbstract:
Allelic polymorphism of the apolipoprotein E (ApoE) gene (ApoE ε2, ApoE ε3 and ApoE ε4 alleles) gives rise to three protein isoforms (ApoE2, ApoE3 and ApoE4) that differ by 1 or 2 amino acids. Inheritance of the ApoE ε4 allele is a risk factor for developing Alzheimer's disease (AD). The potential diagnostic value of ApoE protein levels in biological fluids (i.e. cerebrospinal fluid, plasma and serum) for distinguishing between AD patients and healthy elderly subjects is subject to great controversy. Although a recent study reported subnormal total ApoE and ApoE4 levels in the plasma of AD patients, other studies have found normal or even elevated protein levels (versus controls). Because all previously reported assays were based on immunoenzymatic techniques, we decided to develop an orthogonal assay based on targeted mass spectrometry by tracking (i) a proteotypic peptide common to all ApoE isoforms and (ii) a peptide that is specific for the ε4 allele. After trypsin digestion, the ApoE4-specific peptide contains an oxidation-prone methionine residue. The endogenous methionine oxidation level was evaluated in a small cohort (n = 68) of heterozygous ε3ε4 carriers containing both healthy controls and AD patients. As expected, the proportion of oxidized residues varied from 0 to 10%, with an average of 5%. We therefore developed a standardized strategy for the unbiased, absolute quantification of ApoE4, based on performic acid oxidization of methionine. Once the sample workflow had been thoroughly validated, it was applied to the concomitant quantification of total ApoE and ApoE4 isoform in a large case-control study (n = 669). The final measurements were consistent with most previously reported ApoE concentration values and confirm the influence of the different alleles on the protein expression level. Our results illustrate (i) the reliability of selected reaction monitoring-based assays and (ii) the value of the oxidization step for unbiased monitoring of methionine-containing proteotypic peptides. Furthermore, a statistical analysis indicated that neither total ApoE and ApoE4 levels nor the ApoE/ApoE4 ratio correlated with the diagnosis of AD. These findings reinforce the conclusions of previous studies in which plasma ApoE levels had no obvious clinical significance.
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Sae-Lee, Wisath, Luisa L. Scott, Lotti Brose, Aliyah J. Encarnacion, Ted Shi, Pragati Kore, Lashaun O. Oyibo, Congxi Ye, Susan K. Rozmiarek, and Jonathan T. Pierce. "APP-Induced Patterned Neurodegeneration Is Exacerbated by APOE4 in Caenorhabditis elegans." G3: Genes|Genomes|Genetics 10, no. 8 (June 24, 2020): 2851–61. http://dx.doi.org/10.1534/g3.120.401486.
Full textAbstract:
Genetic and epidemiological studies have found that variations in the amyloid precursor protein (APP) and the apoliopoprotein E (APOE) genes represent major modifiers of the progressive neurodegeneration in Alzheimer’s disease (AD). An extra copy of or gain-of-function mutations in APP correlate with early onset AD. Compared to the other variants (APOE2 and APOE3), the ε4 allele of APOE (APOE4) hastens and exacerbates early and late onset forms of AD. Convenient in vivo models to study how APP and APOE4 interact at the cellular and molecular level to influence neurodegeneration are lacking. Here, we show that the nematode C. elegans can model important aspects of AD including age-related, patterned neurodegeneration that is exacerbated by APOE4. Specifically, we found that APOE4, but not APOE3, acts with APP to hasten and expand the pattern of cholinergic neurodegeneration caused by APP. Molecular mechanisms underlying how APP and APOE4 synergize to kill some neurons while leaving others unaffected may be uncovered using this convenient worm model of neurodegeneration.
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James, Niaya, Oyinkansola Shonde, Nahdia Jones, Verona E. Mulgrave, G. William Rebeck, and Joanne Allard. "Impact of APOE Genotype on Diet-induced Mitochondrial Adaptations in Mouse Skeletal Muscle." Innovation in Aging 5, Supplement_1 (December 1, 2021): 971. http://dx.doi.org/10.1093/geroni/igab046.3496.
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Abstract Apolipoprotein E (APOE), a component of lipoproteins that facilitates cholesterol transportation, has three variants in the human genome: APOE2, E3, and E4. Prior research found that carriers of APOE4 are more susceptible to developing Alzheimer's disease (AD) and other brain disorders than those who possess other APOE alleles, and that these carriers are also predisposed to mitochondrial impairment– an early characteristic of neuronal dysfunction. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1ɑ) is a major biomarker for mitochondrial biogenesis and function and cytochrome c oxidase subunit IV (COX4) is the terminal enzyme of the mitochondrial respiratory chain. Decreased measures of these proteins indicate reduced mitochondrial function. Aside from genetic inheritance, lifestyle factors such as diet and exercise significantly impact one’s risk for mitochondrial dysfunction and AD. In these studies, we examined the impact of APOE variance on physiological adaptations induced by either exercise or a high-fat diet, with a focus on biomarkers of mitochondrial function. Western blots were used to measure COX4 and PGC-1ɑ levels in skeletal muscle tissue from female APOE3 and APOE4 knock-in transgenic mice. Based on performance on a motorized rotating rod and voluntary wheel-running, we deduced that female APOE4 mice exhibit reduced motor coordination and activity relative to APOE3 mice. APOE4 mice also had reduced COX4 levels that were increased by the high-fat diet. In contrast, COX4 levels in APOE3 mice were reduced in the high-fat diet group. Our data show that diet and APOE genotype interact to produce adaptations in mitochondrial proteins in skeletal muscle.
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BENTLEY, Nicholas M., Mary Jo LaDU, Chandrika RAJAN, Godfrey S. GETZ, and Catherine A. REARDON. "Apolipoprotein E structural requirements for the formation of SDS-stable complexes with β-amyloid-(1–40): the role of salt bridges." Biochemical Journal 366, no. 1 (August 15, 2002): 273–79. http://dx.doi.org/10.1042/bj20020207.
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Of the three major isoforms of human apolipoprotein E (apoE), apoE4 is a risk factor for the development of Alzheimer's disease. Among possible neurologically relevant differences in the properties of apoE3 and apoE4 is the fact that apoE3 forms an SDS-stable complex with β-amyloid-(1–40) (Aβ40) with greater avidity than does apoE4. This interaction may sequester potentially toxic species of Aβ or facilitate clearance. To understand more about this difference, we examined whether differences in salt bridges between apoE domains influence the capacity of apoE isoforms to form complexes with Aβ. In apoE3 there is a salt bridge between Arg-61 and Asp-65, while in apoE4 there are salt bridges between Arg-61 and Glu-255, and Arg-112 and Glu-109. Mutation of position 112, which is Cys in apoE3 and Arg in apoE4, to Ala or Lys abolished complex formation, while mutant apoE with Ser at this position retained the capacity to form complex. Substituting Ala for Glu-109 had no effect on the ability of either apoE4 or apoE3 to form complexes. On the other hand, substitution of Thr for Arg-61 in apoE3 abolished, and truncation of apoE3 at position 201 substantially lowered, but did not abolish, complex formation. Neither of these mutations within apoE4 had any affect on its complex formation with Aβ. These results suggest that the nature of the cysteine residue in apoE3 and interactions between the N-terminal and C-terminal domains of human apoE are important for the ability of apoE3 to form an SDS-stable complex with Aβ40.
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Alagarsamy, Jeyashree, Anja Jaeschke, and David Y. Hui. "Apolipoprotein E in Cardiometabolic and Neurological Health and Diseases." International Journal of Molecular Sciences 23, no. 17 (August 31, 2022): 9892. http://dx.doi.org/10.3390/ijms23179892.
Full textAbstract:
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer’s disease. The human APOE gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The APOE gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.
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Tai, Leon M., Katherine L. Youmans, Lisa Jungbauer, Chunjiang Yu, and Mary Jo LaDu. "Introducing HumanAPOEinto AβTransgenic Mouse Models." International Journal of Alzheimer's Disease 2011 (2011): 1–9. http://dx.doi.org/10.4061/2011/810981.
Full textAbstract:
Apolipoprotein E (apoE) and apoE/amyloid-β(Aβ) transgenic (Tg) mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type,apoE−/−mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for Aβ-independent apoE effects on neurodegeneration. To determine the effects of apoE on Aβ-induced neuropathology,apoE−/−mice were crossed with Aβ-Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice withapoE−/−/Aβ-Tg mice further delayed plaque deposition, which eventually developed in apoE4/Aβ-Tg mice prior to apoE3/Aβ-Tg. One approach to address hAPOE-induced temporal delay in Aβpathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with Aβ-Tg mice that have rapid-onset Aβpathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/Aβ-Tg mice. Thus, tractable models for human-apoE/Aβ-Tg mice continue to evolve.
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Burgos, Javier S., Carlos Ramirez, Isabel Sastre, and Fernando Valdivieso. "Effect of Apolipoprotein E on the Cerebral Load of Latent Herpes Simplex Virus Type 1 DNA." Journal of Virology 80, no. 11 (June 1, 2006): 5383–87. http://dx.doi.org/10.1128/jvi.00006-06.
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ABSTRACT Herpes simplex virus type 1 (HSV-1) is neurotropic and enters a latent state lasting the lifetime of the host. This pathogen has recently been proposed as a risk factor for Alzheimer's disease (AD) in conjunction with apolipoprotein E4 (ApoE4). In a murine acute infection model, we showed that viral neuroinvasiveness depends directly on the overall ApoE dosage and especially on the presence of isoform ApoE4. If an interaction between ApoE and HSV-1 is involved in AD, it may occur during latency rather than during acute infection. Certainly, ApoE plays an important role in late-onset AD, i.e., at a time in life when the majority of people harbor HSV-1 in their nervous system. In the present work, wild-type, APOE knockout, APOE3, and APOE4 transgenic mice were used to analyze the influence of the ApoE profile on the levels of latent virus DNA. The knockout mice had significantly lower concentrations of the virus in the nervous system than the wild-type mice, while the APOE4 mice had very high levels in the brain compared to the APOE3 animals. ApoE4 seems to facilitate HSV-1 latency in the brain much more so than ApoE3. The APOE dosage correlated directly with the HSV-1 DNA concentration in the brain, strengthening the hypothesis that HSV-1, together with ApoE, might be involved in AD.
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Ohm, Thomas G., Ulrike Hamker, Angel Cedazo-Minguez, Wolfgang Röckl, Hubert Scharnagl, Winfried März, Richard Cowburn, Wolfgang Müller, and Volker Meske. "Apolipoprotein E and ϐA4-amyloid: signals and effects." Biochemical Society Symposia 67 (February 1, 2001): 121–29. http://dx.doi.org/10.1042/bss0670121.
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In humans, the apolipoprotein E gene (APOE) is polymorphic with the alleles APOE ϵ2, 3 and 4 coding for apolipoproteins (Apo) E2, 3 and 4. Apart from age, the APOE ϵ4 allele represents the most important risk factor in sporadic Alzheimer's disease (AD). Compared to APOE ϵ3 homozygotes, the histopathological onset of tau pathology is found 1-2 decades earlier but progresses with the same speed. ApoE dose-dependently and specifically increases free intraneuronal calcium levels in the order ApoE4 > ApoE3 > ApoE2. This effect is amplified in the presence of ϐA4-peptide. The ApoE effects on calcium are not affected by the blockade of action potentials with tetrodotoxin, or by inhibition of common ApoE binding sites. The calcium channel involved has been identified as a P/Q-type-like channel. Brain tissue ApoE levels differ with respect to APOE alleles and Braak-stage for Alzheimer-histopathology. The production of ApoE in astrocytes is controlled by several receptor/effector systems such as adrenoceptors and cAMP. In the presence of ϐA4-peptide fragments, astrocytes stop their synthesis of ApoE resulting in a massive reduction in the bioavailability of ApoE. In the periphery, ApoE directs cholesterol transport and thereby influences its cellular concentrations. In neurons, changes in the concentration of cholesterol influence the phosphorylation status of the microtubule-associated protein tau at sites known to be altered in AD.
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Hsu, Michelle, Mehek Dedhia, Wim E. Crusio, and Anna Delprato. "Sex differences in gene expression patterns associated with the APOE4 allele." F1000Research 8 (July 23, 2019): 387. http://dx.doi.org/10.12688/f1000research.18671.2.
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Background: The APOE gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the APOE gene: APOE2, APOE3, and APOE4. The APOE4 allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. Methods: In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the APOE4 allele in order to identify possible sex-related differences that may be relevant to AD. Results: Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of APOE in APOE4-positive individuals. The number of these genes was much higher in APOE4-positive females than in APOE4-positive males, who in turn had more of such genes than APOE4-negative control groups. Our findings also indicate a significant sex* genotype interaction for the CNTNAP2 gene, a member of the neurexin family and a significant interaction for brain area*sex* genotype for PSEN2, a risk factor gene for AD. Conclusions: Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of APOE with respect to sex differences and AD.
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Koren-Iton, Amit, Shiran Salomon-Zimri, Alex Smolar, Efrat Shavit-Stein, Amir Dori, Joab Chapman, and Daniel M. Michaelson. "Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology." International Journal of Molecular Sciences 21, no. 4 (February 14, 2020): 1289. http://dx.doi.org/10.3390/ijms21041289.
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Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.
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TOKUDA, Takahiko, Miguel CALERO, Etsuro MATSUBARA, Ruben VIDAL, Asok KUMAR, Bruno PERMANNE, Berislav ZLOKOVIC, et al. "Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid β peptides." Biochemical Journal 348, no. 2 (May 23, 2000): 359–65. http://dx.doi.org/10.1042/bj3480359.
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The inheritance of the apolipoprotein E (apoE) ϵ4 allele is a prevailing risk factor for sporadic and familial Alzheimer's disease (AD). ApoE isoforms bind directly to Alzheimer's amyloid β (Aβ) peptides both in vitro and in vivo. Recent studies suggest that association of apoE with lipids may modulate its interaction with Aβ. We examined the binding of lipid-associated and delipidated apoE3 and apoE4 isoforms to Aβ utilizing a solid-phase binding assay and estimated the dissociation constants for the interaction of various apoE and Aβ species. Using native apoE isoforms from stably transfected RAW 264 and human embryonic kidney 293 cells, apoE3 had greater affinity than apoE4 for both Aβ1-40 and Aβ1-42. Delipidation of apoE decreased its affinity for Aβ peptides by 5-10-fold and abolished the isoform-specificity. Conversely, incorporation of apoE isoforms produced by baculovirus-infected Sf9 cells into reconstituted human high-density-lipoprotein lipoparticles restored the affinity values for Aβ peptides and resulted in preferential binding of apoE3. The data demonstrate that native lipid-associated apoE3 binds to Aβ peptides with 2-3-fold higher affinity than lipid-associated apoE4. Since the isoforms' binding efficiency correlate inversely with the risk of developing late-onset AD, the results suggest a possible involvement of apoE3 in the clearance or routing out of Aβ from the central nervous system as one of the mechanisms underlying the pathology of the disease.
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Washington, Patricia M., and Mark P. Burns. "The Effect of the APOE4 Gene on Accumulation of Aβ 40 After Brain Injury Cannot Be Reversed by Increasing apoE4 Protein." Journal of Neuropathology & Experimental Neurology 75, no. 8 (June 11, 2016): 770–78. http://dx.doi.org/10.1093/jnen/nlw049.
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Abstract The apolipoprotein E (apoE) protein is involved in clearance of β-amyloid (Aβ) from the brain; and the APOE4 gene is associated with Aβ plaque formation in humans following traumatic brain injury (TBI). Here, we examined the association between apoE and Aβ 40 after experimental TBI and the effects of APOE alleles on this relationship. We report a biphasic response of soluble apoE protein after TBI with an acute reduction at 1 day postinjury followed by an increase at 7 days postinjury. TBI-induced Aβ 40 levels decreased as soluble apoE levels increased. In APOE4 mice there was a diminished apoE response to TBI that corresponded to prolonged accumulation of TBI-induced Aβ 40 versus that in APOE3 mice. Amyloid precursor protein processing was similar in APOE3 and APOE4 mice suggesting that impaired clearance was responsible for the abnormal accumulation of Aβ 40 in the latter. Treatment of APOE4 mice with bexarotene for 7 days increased apoE4 protein levels but was not sufficient to reduce TBI-induced Aβ 40 . Thus, rapid clearance of TBI-induced Aβ 40 occurs in mice but these pathways are impaired in APOE4 carriers. These data may help explain the deposition of Aβ in APOE4 carriers and the increased incidence of brain Aβ plaques following TBI.
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Mai, Zhenhua, Wenyan Wei, Haibin Yu, Yongze Chen, Yongxiang Wang, and Yuanlin Ding. "Molecular recognition of the interaction between ApoE and the TREM2 protein." Translational Neuroscience 13, no. 1 (January 1, 2022): 93–103. http://dx.doi.org/10.1515/tnsci-2022-0218.
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Abstract Alzheimer’s disease (AD) is the most common type of dementia. The ε4 allele of the apolipoprotein E (ApoE) gene is the strongest known genetic risk factor for late-onset AD. Triggering receptor expressed on myeloid cells 2 (TREM2) is another important risk factor affecting the AD process after ApoE. Emerging evidence has identified TREM2 as a putative receptor for ApoE, raising the possibility that interactions between ApoE and TREM2 modulate the pathogenesis of AD. In this study, we performed molecular docking and molecular dynamics (MD) analyses to characterize the ApoE–TREM2 interaction and further investigated the effect of the major TREM2 disease-associated mutation (R47H) on the affinity of TREM2 for ApoE. The results indicate that the binding energy between ApoE and TREM2 occurs in an isoform-dependent manner with the following potency rank order: ApoE4 > ApoE3 > ApoE2. In addition, the R47H mutant reduced the interaction between ApoE and TREM2 protein, which may be attributed to decreased hydrogen-bonding interactions, hydrophobic interactions, and electrostatic forces between ApoE and TREM2. Our study analyzed the molecular pattern of the interactions between ApoE and TREM2 and how the variants affect these interactions based on in silico modeling, and the results might help to elucidate the interaction mechanism between ApoE and TREM2. Additional experimental studies will be needed to verify and explore the current findings.
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Yamauchi, Kazuyoshi, Minoru Tozuka, Hiroya Hidaka, Eiko Hidaka, Yoshiyuki Kondo, and Tsutomu Katsuyama. "Characterization of Apolipoprotein E-containing Lipoproteins in Cerebrospinal Fluid: Effect of Phenotype on the Distribution of Apolipoprotein E." Clinical Chemistry 45, no. 9 (September 1, 1999): 1431–38. http://dx.doi.org/10.1093/clinchem/45.9.1431.
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Abstract Background: Apolipoprotein (apo) E, one of the main apolipoproteins in the central nervous system, may play an important role in lipid metabolism; however, the details of its function are poorly understood. In this study, we characterized apoE-containing lipoproteins in cerebrospinal fluid (CSF) and examined the effect of apoE phenotype on the distribution of apoE among the lipoprotein fractions. Methods: CSF lipoproteins were fractionated by gel filtration and ultracentrifugation, and then characterized by electrophoresis, immunoblot, electron microscopy, and analysis of apoE, total cholesterol, and phospholipid concentrations. Results: The ratio of sialylated to nonsialylated apoE was higher in CSF than in serum. However, the fundamental forms containing apoE homodimers or heterodimers [such as apo(E-AII) and apo(AII-E2-AII) complexes] were similar in CSF and serum. apoE-containing lipoproteins were fractionated at densities of <1.006, 1.063–1.125, and 1.125–1.21 kg/L. Neither apoE nor apoAI was detected in the fraction with a density range of 1.006–1.063 kg/L. The diameters of the lipoprotein particles with densities of <1.006, 1.063–1.125, and 1.125–1.21 kg/L were 16.7 ± 3.1, 14.0 ± 3.2, and 11.6 ± 2.8 nm (mean ± SD, n = 200), respectively. All of these lipoproteins exhibited a spherical structure. The distribution profile of apoE-containing lipoproteins was affected by the apoE phenotype. A relatively large amount of apoE-containing lipoproteins was isolated from the fraction with a density >1.125 kg/L obtained from CSF associated with apoE2 or apoE3. This tendency was more obvious in CSF associated with apoE2 than in CSF without apoE2. apoE-containing lipoproteins were predominantly observed in the fraction with a density of <1.006 kg/L obtained from CSF associated with apoE4. Conclusions: The lipoproteins in CSF have a unique composition that is different from that of the lipoproteins in plasma. However, the differences in diameter between the CSF fractions were not as large as for the serum fractions. Our data suggest that the apoE phenotype may affect the distribution profile of apoE-containing lipoproteins in the CSF. This would mean that the metabolism of apoE-containing lipoproteins depends on the apoE isoform present.
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Shinohara, Mitsuru, Kaoru Suzuki, Guojun Bu, and Naoyuki Sato. "Interaction Between APOE Genotype and Diabetes in Longevity." Journal of Alzheimer's Disease 82, no. 2 (July 21, 2021): 719–26. http://dx.doi.org/10.3233/jad-210125.
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Background: While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer’s disease, their relationship remains to be elucidated. Objective: The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. Methods: We reviewed the National Alzheimer’s Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Results: Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17–1.42, p < 0.001) and APOE2 carriers (n = 2,390, HR = 1.37, 95%CI = 1.10–1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n = 9,490, HR = 1.11, 95%CI = 0.99–1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p < 0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. Conclusion: The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.
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Zhou, Y., and G. Luo. "Apolipoproteins, as the carrier proteins for lipids, are involved in the development of breast cancer." Clinical and Translational Oncology 22, no. 11 (April 18, 2020): 1952–62. http://dx.doi.org/10.1007/s12094-020-02354-2.
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Abstract Apolipoproteins, the key components of lipoproteins, play vital roles in the combination and transportation of lipids. Numerous research articles have accumulated solid evidence that lipoproteins are closely related to various types of tumorigenesis. In this review, we focused on the associations between several apolipoproteins and breast carcinoma and distinguished the effects and significance of apolipoproteins in different locations to validate their roles in breast carcinoma development. For example, apoD and apoE in serum are viewed as risk factors for breast carcinoma. ApoD, apoE and apoA-I in mammary tissues inhibit tumor growth. Moreover, apoB, apoJ and apoA-I have the potential to function as diagnostic or prognostic markers in the clinic. ApoEdp and apoJ treatment on breast carcinoma could significantly restrict tumor growth. In general, the aim of this review was to further analyze the associations between some members of the apolipoprotein family and breast cancer.
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Usman, Elly, Gestina Aliska, and Masrul Syafri. "Correlation of ApoE Gene Polymorphism with Coronary Heart Disease Severity in Patients with Acute Coronary Syndrome Who Receive Statin Therapy, Padang, Indonesia." Journal of Midwifery 7, no. 1 (July 30, 2022): 1. http://dx.doi.org/10.25077/jom.7.1.1-7.2022.
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Coronary Heart Disease (CHD) is still the most common cause of death. Ischemic heart disease causes more than 7 million (12.8%) deaths worldwide. It is estimated that 3,750,000 Indonesians have CHD. CHD is a disease with many risk factors. ApoE gene polymorphism is associated with atherosclerosis and plays a role in lipid metabolism, which is 2-16% affecting variability in LDL levels. This study aims to look at the relationship between ApoE gene polymorphism and the severity of coronary heart disease. Data regarding ApoE gene polymorphism was obtained using polymerase chain reaction (PCR). DNA was isolated from white blood cells using DNA purification kit. ApoE2, ApoE3, ApoE4 alleles were detected by DNA sequencing. Data on the severity of coronary heart disease were obtained from angiography and were calculated based on SYNTAX scores. In this study, ApoE was obtained with e2 allele frequencies (4.63%), e3 (78.70%), and e4 (16.67%) with E2 / 2 (0%), E2 / 3 (3.70%), E2 / 4 (5.56%), E3 / 3 (64.81%), E3 / 4 (24.07%), and E4 / 4 (1.85%). The relationship between the SYNTAX score and the ApoE genotype has no significant difference. ApoE3 / 4 genotype has the highest SYNTAX score and the e4 allele has the most influence on CHD despite the influence of statin therapy.
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Kypreos, Kyriakos E., and Vassilis I. Zannis. "Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT." Biochemical Journal 403, no. 2 (March 26, 2007): 359–67. http://dx.doi.org/10.1042/bj20061048.
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We have investigated the ability of apoE (apolipoprotein E) to participate in the biogenesis of HDL (high-density lipoprotein) particles in vivo using adenovirus-mediated gene transfer in apoA-I−/− (apolipoprotein A-I) or ABCA1−/− (ATP-binding cassette A1) mice. Infection of apoA-I−/− mice with 2×109 pfu (plaque-forming units) of an apoE4-expressing adenovirus increased both HDL and the triacylglycerol-rich VLDL (very-low-density lipoprotein)/IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein) fraction and generated discoidal HDL particles. ABCA1−/− mice treated similarly failed to form HDL particles, suggesting that ABCA1 is essential for the generation of apoE-containing HDL. Combined infection of apoA-I−/− mice with a mixture of adenoviruses expressing both apoE4 (2×109 pfu) and human LCAT (lecithin:cholesterol acyltransferase) (5×108 pfu) cleared the triacylglycerol-rich lipoproteins, increased HDL and converted the discoidal HDL into spherical HDL. Similarly, co-infection of apoE−/− mice with apoE4 and human LCAT corrected the hypercholesterolaemia and generated spherical particles, suggesting that LCAT is essential for the maturation of apoE-containing HDL. Overall, the findings indicate that apoE has a dual functionality. In addition to its documented functions in the clearance of triacylglycerol-rich lipoproteins, it participates in the biogenesis of HDL-sized apoE-containing particles. HDL particles generated by this pathway may account at least for some of the atheroprotective functions of apoE.
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Jofre-Monseny, Laia, Sonia de Pascual-Teresa, Eva Plonka, Patricia Huebbe, Christine Boesch-Saadatmandi, Anne-Marie Minihane, and Gerald Rimbach. "Differential effects of apolipoprotein E3 and E4 on markers of oxidative status in macrophages." British Journal of Nutrition 97, no. 5 (May 2007): 864–71. http://dx.doi.org/10.1017/s0007114507669219.
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ApoE is secreted by macrophages at the lesion site of the atherosclerotic plaque, where it is thought to play a protective role against atherosclerosis independently of its effects on lipid metabolism. Of the three common isoforms for apoE, apoE4 is associated with higher risk of cardiovascular disease (CVD). In vitro studies have shown that recombinant apoE may act as an antioxidant in an isoform-dependent manner (E2>E3>E4). The oxidative status of the macrophages plays a key role in the process of atherosclerosis. In the present study the possible differential actions of apoE3 and apoE4 on several parameters of oxidative status were determined in stably transfected murine macrophages (RAW 264·7-apoE3 and -apoE4). No differences between genotypes were observed after peroxide challenge in either protection against cytotoxicity or in cell membrane oxidation, and modest differences were observed in the non-enzymatic antioxidants (glutathione and α-tocopherol) in apoE3 v. apoE4 macrophages. Importantly, cells secreting apoE4 showed increased membrane oxidation under basal conditions, and produced more NO and superoxide anion radicals than the apoE3 macrophages after stimulation. The present data suggest that apoE genotype influences the oxidative status of macrophages, and this could partly contribute to the higher CVD risk observed in apoE4 carriers.
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Dafnis, Ioannis, Christina Raftopoulou, Christina Mountaki, Evgenia Megalou, Vassilis I. Zannis, and Angeliki Chroni. "ApoE isoforms and carboxyl-terminal-truncated apoE4 forms affect neuronal BACE1 levels and Aβ production independently of their cholesterol efflux capacity." Biochemical Journal 475, no. 10 (May 31, 2018): 1839–59. http://dx.doi.org/10.1042/bcj20180068.
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The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) initiates the production of amyloid-β peptide (Aβ), which is central to the pathogenesis of Alzheimer's disease (AD). Changes in brain cholesterol homeostasis have been suggested to affect Aβ metabolism. Cholesterol homeostasis is maintained in the brain by apolipoprotein E (apoE). The apoE4 isoform constitutes the major risk factor for AD. Here, we investigated the effect of apoE forms on Aβ generation and on BACE1 levels. We also examined the potential involvement in these processes of cholesterol transporters ABCG1 and ABCG4 or the lipoprotein receptor SR-BI, which are implicated in cholesterol efflux to apoE. It was found that reconstituted lipoprotein-associated apoE isoforms promoted the increase of Aβ production and oligomerization and of BACE1 levels in human neuroblastoma SK-N-SH cells, with an apoE4 ≥ apoE3 > apoE2 potency rank order. Progressive carboxyl-terminal apoE4 deletions between residues 230–299 decreased the protein's ability to increase BACE1, while further truncations up to residue 166 prevented apoE4 from increasing BACE1 and Aβ levels in SK-N-SH and primary mouse neuronal cells. ABCG1, but not ABCG4 or SR-BI, moderately increased Aβ production and BACE1 levels in SK-N-SH cells. All apoE forms affected Aβ production/oligomerization and BACE1 levels in a pattern that did not follow that of their capacity to promote ABCG1, ABCG4 or SR-BI-mediated cholesterol efflux. Overall, our data indicate that apoE-containing lipoprotein particles can have a direct effect on BACE1 levels and Aβ secretion and possibly contribute to AD pathogenetic processes, independently of their capacity to promote cholesterol efflux.
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Suidan, Georgette L., and Gayathri Ramaswamy. "Targeting Apolipoprotein E for Alzheimer’s Disease: An Industry Perspective." International Journal of Molecular Sciences 20, no. 9 (May 1, 2019): 2161. http://dx.doi.org/10.3390/ijms20092161.
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Apolipoprotein E (apoE), a key lipid transport protein in the brain, is predominantly produced by astrocytes. Astrocytes are the most numerous cell type in the brain and are the main support network for neurons. They play a critical role in the synthesis and delivery of cholesterol in the brain. Humans have three common apoE isoforms, apoE2, apoE3 and apoE4, that show a strong genotype effect on the risk and age of onset for sporadic and late onset forms of Alzheimer’s disease (AD). Carriers of an ε4 allele have an increased risk of developing AD, while those with an ε2 allele are protected. Investigations into the contribution of apoE to the development of AD has yielded conflicting results and there is still much speculation about the role of this protein in disease. Here, we review the opposing hypotheses currently described in the literature and the approaches that have been considered for targeting apoE as a novel therapeutic strategy for AD. Additionally, we provide our perspective on the rationale for targeting apoE and the challenges that arise with respect to “drug-ability” of this target.