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1
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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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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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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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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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.
7
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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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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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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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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Kahri, Juhani, Aino Soro-Paavonen, Christian Ehnholm, and Marja-Riitta Taskinen. "ApoE Polymorphism Is Associated With C-Reactive Protein in Low-HDL Family Members and in Normolipidemic Subjects." Mediators of Inflammation 2006 (2006): 1–5. http://dx.doi.org/10.1155/mi/2006/12587.
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The study was aimed to compare inflammatory parameters between carriers of apoE4 isoforms (apoE4/3, apoE4/2, and apoE4/4 phenotypes) and those of carrying apoE3 isoform without apoE4 isoform (apoE3/3 phenotypes and apoE2/3 phenotypes). The concentrations of serum hsCRP, sVCAM-1, sICAM-1, and sE-selectin were measured in 211 subjects from Finnish low-HDL families and in 157 normolipidemic subjects. The subjects with apoE4 isoform had lower concentrations of serum hsCRP both in low-HDL family members (p<0.05) and in normolipidemic subjects (p<0.01). The differences in serum CRP values remained significant after adjustment for age, BMI, smoking status, hypertension, gender, lipoprotein variables, and family number. We conclude that apoE phenotype has a strong influence on serum CRP values.
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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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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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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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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.
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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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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.
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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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Frieden, Carl, Hanliu Wang, and Chris M. W. Ho. "A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain–domain interactions." Proceedings of the National Academy of Sciences 114, no. 24 (May 30, 2017): 6292–97. http://dx.doi.org/10.1073/pnas.1705080114.
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Relative to the apolipoprotein E (apoE) E3 allele of the APOE gene, apoE4 strongly increases the risk for the development of late-onset Alzheimer’s disease. However, apoE4 differs from apoE3 by only a single amino acid at position 112, which is arginine in apoE4 and cysteine in apoE3. It remains unclear why apoE3 and apoE4 are functionally different. Described here is a proposal for understanding the functional differences between these two isoforms with respect to lipid binding. A mechanism is proposed that is based on the full-length monomeric structure of the protein, on hydrogen–deuterium exchange mass spectrometry data, and on the role of intrinsically disordered regions to control protein motions. It is proposed that lipid binds between the N-terminal and C-terminal domains and that separation of the two domains, along with the presence of intrinsically disordered regions, controls this process. The mechanism explains why apoE3 differs from apoE4 with respect to different lipid-binding specificities, why lipid increases the binding of apoE to its receptor, and why specific residues are conserved.
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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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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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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.
Full textAbstract:
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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Zepa, Lia, Moran Frenkel, Haim Belinson, Zehavit Kariv-Inbal, Rakez Kayed, Eliezer Masliah, and Daniel M. Michaelson. "ApoE4-Driven Accumulation of Intraneuronal Oligomerized Aβ42 following Activation of the Amyloid CascadeIn VivoIs Mediated by a Gain of Function." International Journal of Alzheimer's Disease 2011 (2011): 1–8. http://dx.doi.org/10.4061/2011/792070.
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Activating the amyloid cascade by inhibiting the Aβ-degrading enzyme neprilysin in targeted replacement mice, which express either apoE4 or apoE3, results in the specific accumulation of oligomerized Aβ42 in hippocampal CA1 neurons of the apoE4 mice. We presently investigated the extent to which the apoE4-driven accumulation of Aβ42 and the resulting mitochondrial pathology are due to either gain or loss of function. This revealed that inhibition of neprilysin for one week triggers the accumulation of Aβ42 in hippocampal CA1 neurons of the apoE4 mice but not of either the corresponding apoE3 mice or apoE-deficient mice. At 10 days, Aβ42 also accumulated in the CA1 neurons of the apoE-deficient mice but not in those of the apoE3 mice. Mitochondrial pathology, which in the apoE4 mice is an early pathological consequence following inhibition of neprilyisn, also occurs in the apoE-deficient but not in the apoE3 mice and the magnitude of this effect correlates with the levels of accumulated Aβ42 and oligomerized Aβ42 in these mice. These findings suggest that the rate-limiting step in the pathological effects of apoE4 on CA1 neurons is the accumulation of intracellular oligomerized Aβ42 which is mediated via a gain of function property of apoE4.
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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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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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Moreno, Juan Antonio, Francisco Pérez-Jiménez, Rafael Moreno-Luna, Pablo Pérez-Martínez, Francisco Fuentes-Jiménez, Carmen Marín, Henri Portugal, Denis Lairon, and José López-Miranda. "The effect ofapoEgenotype and sex on ApoE plasma concentration is determined by dietary fat in healthy subjects." British Journal of Nutrition 101, no. 12 (November 24, 2008): 1745–52. http://dx.doi.org/10.1017/s0007114508111515.
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The interindividual variation in ApoE plasma concentration is considerable, mainly determined byapoEgenotype and sex. However, a large amount of variability remains unexplained by these factors. We have evaluated whether the quantity and quality of dietary fat interacts with theapoEgenotype and sex modifying ApoE plasma levels in young healthy subjects. Eighty-four volunteers (sixty-six apoE3/3, eight apoE4/3 and ten apoE3/2) were subjected to three dietary periods, each lasting 4 weeks. The first was a SFA-enriched diet (38 % fat and 20 % SFA), which was followed by a carbohydrate (CHO)-rich diet (30 % fat, < 10 % SFA and 55 % carbohydrate) or a MUFA-rich diet (38 % fat and 22 % MUFA) following a randomised crossover design.apoE2carriers have the highest ApoE levels, whereasapoE4individuals show the lowest concentration after the SFA, CHO and MUFA diets. Women had significantly higher ApoE concentration than men only after the consumption of the SFA diet. The SFA diet increased the ApoE plasma concentration when compared with the CHO- and MUFA-rich diets in women, but not in men. In women, but not in men, the shift from the SFA- to CHO- or MUFA-rich diets significantly decreased the ApoE concentration in apoE3/2 and apoE3/3 subjects, whereas no differences were observed in women with the apoE4/3 genotype. Sex andapoEgenotype determine ApoE plasma levels; however, this effect is dependent on dietary fat.
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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.
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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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Halliday, Matthew R., Sanket V. Rege, Qingyi Ma, Zhen Zhao, Carol A. Miller, Ethan A. Winkler, and Berislav V. Zlokovic. "Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease." Journal of Cerebral Blood Flow & Metabolism 36, no. 1 (March 11, 2015): 216–27. http://dx.doi.org/10.1038/jcbfm.2015.44.
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The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 ( APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD ( APOE4 > APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.
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Jofre-Monseny, Laia, Patricia Huebbe, Inken Stange, Christine Boesch-Saadatmandi, Jan Frank, Kim Jackson, Anne-Marie Minihane, and Gerald Rimbach. "Influence of apolipoprotein E genotype and dietary α-tocopherol on redox status and C-reactive protein levels in apolipoprotein E3 and E4 targeted replacement mice." British Journal of Nutrition 100, no. 1 (July 2008): 44–53. http://dx.doi.org/10.1017/s000711450788634x.
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The molecular basis of the positive association between apoE4 genotype and CVD remains unclear. There is direct in vitro evidence indicating that apoE4 is a poorer antioxidant relative to the apoE3 isoform, with some indirect in vivo evidence also available. Therefore it was hypothesised that apoE4 carriers may benefit from α-tocopherol (α-Toc) supplementation. Targeted replacement mice expressing the human apoE3 and apoE4 were fed with a diet poor (0 mg/kg diet) or rich (200 mg/kg diet) in α-Toc for 12 weeks. Neither apoE genotype nor dietary α-Toc exerted any effects on the antioxidant defence system, including glutathione, catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase activities. In addition, no differences were observed in mitogen-induced lymphocyte proliferation. α-Toc concentrations were modestly higher in plasma and lower in tissues of apoE4 compared with apoE3 mice, with the greatest differences evident in the lung, suggesting that an apoE4 genotype may reduce α-Toc delivery to tissues. A tendency towards increased plasma F2-isoprostanes in apoE4 mice was observed, while liver thiobarbituric acid-reactive substances did not differ between apoE3 and apoE4 mice. In addition, C-reactive protein (CRP) concentrations were reduced in apoE4 mice indicating that this positive effect on CRP may in part negate the increased CVD risk associated with an apoE4 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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Keable, Abby, Ronan O’Neill, Matthew MacGregor Sharp, Maureen Gatherer, Ho Ming Yuen, David Annandale Johnston, Roy Oliver Weller, and Roxana Octavia Carare. "ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4371. http://dx.doi.org/10.3390/ijms21124371.
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The accumulation of amyloid-β (Aβ) in the walls of capillaries and arteries as cerebral amyloid angiopathy (CAA) is part of the small vessel disease spectrum, related to a failure of elimination of Aβ from the brain. Aβ is eliminated along basement membranes in walls of cerebral capillaries and arteries (Intramural Peri-Arterial Drainage—IPAD), a pathway that fails with age and ApolipoproteinEε4 (ApoE4) genotype. IPAD is along basement membranes formed by capillary endothelial cells and surrounding astrocytes. Here, we examine (1) the composition of basement membranes synthesised by ApoE4 astrocytes; (2) structural differences between ApoE4 and ApoE3 astrocytes, and (3) how flow of Aβ affects Apo3/4 astrocytes. Using cultured astrocytes expressing ApoE3 or ApoE4, immunofluorescence, confocal, correlative light and electron microscopy (CLEM), and a millifluidic flow system, we show that ApoE4 astrocytes synthesise more fibronectin, possess smaller processes, and become rarefied when Aβ flows over them, as compared to ApoE3 astrocytes. Our results suggest that basement membranes synthesised by ApoE4 astrocytes favour the aggregation of Aβ, its reduced clearance via IPAD, thus promoting cerebral amyloid angiopathy.
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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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Yamazaki, Yu, Mitsuru Shinohara, Akari Yamazaki, Yingxue Ren, Yan W. Asmann, Takahisa Kanekiyo, and Guojun Bu. "ApoE (Apolipoprotein E) in Brain Pericytes Regulates Endothelial Function in an Isoform-Dependent Manner by Modulating Basement Membrane Components." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 1 (January 2020): 128–44. http://dx.doi.org/10.1161/atvbaha.119.313169.
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Objective: The ε4 allele of the APOE gene ( APOE4 ) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. Conclusions: ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.
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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.
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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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Kim, Meewhi, and Ilya Bezprozvanny. "Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis." International Journal of Molecular Sciences 22, no. 9 (May 10, 2021): 5030. http://dx.doi.org/10.3390/ijms22095030.
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Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.
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Zhu, Li, Minghao Zhong, Gregory A. Elder, Mary Sano, David M. Holtzman, Sam Gandy, Christopher Cardozo, Vahram Haroutunian, Nikolaos K. Robakis, and Dongming Cai. "Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis." Proceedings of the National Academy of Sciences 112, no. 38 (September 8, 2015): 11965–70. http://dx.doi.org/10.1073/pnas.1510011112.
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The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.
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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.
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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. 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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Edlund, Anna K., Kewei Chen, Wendy Lee, Hillary Protas, Yi Su, Eric Reiman, Richard Caselli, and Henrietta M. Nielsen. "Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers." Journal of Alzheimer's Disease 81, no. 1 (May 4, 2021): 339–54. http://dx.doi.org/10.3233/jad-210065.
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Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.
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Demby, Tamar, G. William Rebeck, Christopher Albanese, Olga C. Rodriguez, Yichien Lee, and Jeanne Mandelblatt. "3367 A Mouse Model of APOE Genotype in Chemotherapy Related Cognitive Impairment." Journal of Clinical and Translational Science 3, s1 (March 2019): 1. http://dx.doi.org/10.1017/cts.2019.6.
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OBJECTIVES/SPECIFIC AIMS: Chemotherapy-related cognitive impairment (CRCI) affects 15-35% of breast cancer survivors and constitutes a significant challenge for survivor quality of life. Among older breast cancer survivors who received chemotherapy treatment, carriers of at least one ɛ4 allele of the APOE gene, which encodes apolipoprotein E, are at higher risk for developing CRCI than non-carriers. APOE4 is well characterized as the strongest genetic risk factor for Alzheimer’s disease, but how it contributes to CRCI is not yet understood, and no animal models of APOE genotype and CRCI have yet been established. To better understand how APOE4 acts as a risk factor for CRCI, we used APOE targeted replacement (TR) mice to develop a model of its effects on cognition following treatment with doxorubicin, a chemotherapy drug commonly used in breast cancer treatment. METHODS/STUDY POPULATION: Twelve-to-thirteen month old APOE3 and APOE4 targeted replacement mice expressing human APOE3 or human APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or equivolume saline given via two IP injections spaced one week apart. One week post-treatment, mice were tested using Open Field and Elevated Zero apparatuses to assess baseline locomotive activity and anxiety and exploratory behaviors. Five weeks post-treatment, mice were assessed using the Barnes Maze over four days of training trials and one 72 hour memory probe. RESULTS/ANTICIPATED RESULTS: We found no differences in Open Field and Elevated Zero behavior, indicating limited influence of doxorubicin treatment on locomotive and anxiety behaviors in both genotypes. During Barnes Maze training, APOE4 mice treated with doxorubicin showed increased latency compared to untreated APOE4 mice as well as treated and untreated APOE3 mice, indicating deficiencies in spatial learning. In APOE3 mice, no differences in performance were seen between doxorubicin-treated and untreated mice (n = 15-16/group, p <.0001). DISCUSSION/SIGNIFICANCE OF IMPACT: These results indicate that APOE4 targeted replacement mice have specific cognitive vulnerabilities to doxorubicin treatment that can be reliably detected using the Barnes Maze assessment. Future directions include experiments to determine how other chemotherapy drugs or drug combinations impact cognition of APOE4 mice. Ultimately this model may be used to assess preventive measures or therapies for CRCI in the vulnerable APOE4 carrier population with the ability to validate cognitive impacts of these interventions.
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Chetty, Palaniappan S., Leland Mayne, Sissel Lund-Katz, S. Walter Englander, and Michael C. Phillips. "Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry." Proceedings of the National Academy of Sciences 114, no. 5 (January 17, 2017): 968–73. http://dx.doi.org/10.1073/pnas.1617523114.
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Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer’s disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen−deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution. We determined the positions, dynamics, and stabilities of the helical segments in these two proteins, in their normal tetrameric state and in mutation-induced monomeric mutants. Consistent with prior X-ray crystallography and NMR results, the N-terminal domain contains four α-helices, 20 to 30 amino acids long. The C-terminal domain is relatively unstructured in the monomeric state but forms an α-helix ∼70 residues long in the self-associated tetrameric state. Helix stabilities are relatively low, 4 kcal/mol to 5 kcal/mol, consistent with flexibility and facile reversible unfolding. Secondary structure in the tetrameric apoE3 and E4 isoforms is similar except that some helical segments in apoE4 spanning residues 12 to 20 and 204 to 210 are unfolded. These conformational differences result from the C112R substitution in the N-terminal helix bundle and likely relate to a reduced ability of apoE4 to form tetramers, thereby increasing the concentration of functional apoE4 monomers, which gives rise to its higher lipid binding compared with apoE3.
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Watson, Yassin, Brenae Nelson, Jamie Hernandez Kluesner, Caroline Tanzy, Shreya Ramesh, Zoey Patel, Kaci Hernandez Kluesner, Anita Singh, Vibha Murthy, and Cassie S. Mitchell. "Aggregate Trends of Apolipoprotein E on Cognition in Transgenic Alzheimer’s Disease Mice." Journal of Alzheimer's Disease 83, no. 1 (August 31, 2021): 435–50. http://dx.doi.org/10.3233/jad-210492.
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Background: Apolipoprotein E (APOE) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer’s disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord. Objective: Analysis of 31 peer-reviewed AD APOE mouse publications (n = 3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition. Methods: T-tests with Bonferroni correction (significance = p < 0.002) compared age-normalized Morris water maze (MWM) escape latencies in wild type (WT), APOE2 knock-in (KI2), APOE3 knock-in (KI3), APOE4 knock-in (KI4), and APOE knock-out (KO) mice. Positive treatments (t+) to favorably modulate APOE to improve cognition, negative treatments (t–) to perturb etiology and diminish cognition, and untreated (t0) mice were compared. Machine learning with random forest modeling predicted MWM escape latency performance based on 12 features: mouse genotype (WT, KI2, KI3, KI4, KO), modulatory treatment (t+, t–, t0), mouse age, and mouse gender (male = g_m; female = g_f, mixed gender = g_mi). Results: KI3 mice performed significantly better in MWM, but KI4 and KO performed significantly worse than WT. KI2 performed similarly to WT. KI4 performed significantly worse compared to every other genotype. Positive treatments significantly improved cognition in WT, KI4, and KO compared to untreated. Interestingly, negative treatments in KI4 also significantly improved mean MWM escape latency. Random forest modeling resulted in the following feature importance for predicting superior MWM performance: [KI3, age, g_m, KI4, t0, t+, KO, WT, g_mi, t–, g_f, KI2] = [0.270, 0.094, 0.092, 0.088, 0.077, 0.074, 0.069, 0.061, 0.058, 0.054, 0.038, 0.023]. Conclusion: APOE3, age, and male gender was most important for predicting superior mouse cognitive performance.
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Liu, Min, David G. Kuhel, Ling Shen, David Y. Hui, and Stephen C. Woods. "Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 9 (November 1, 2012): R903—R908. http://dx.doi.org/10.1152/ajpregu.00219.2012.
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Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is important in lipoprotein metabolism both peripherally and centrally. Because it is primarily produced in the liver, apoE observed in the brain or cerebrospinal fluid (CSF) could have originated in the periphery; i.e., circulating apoE may cross the blood-brain barrier (BBB) and/or enter CSF and be taken up by brain cells. To determine whether this occurs, a second-generation adenovirus encoding human apoE3 was administered intravenously (iv) to C57BL/6J mice, and the detection of human apoE3 in the CSF was used as a surrogate measure of central availability of this protein utilizing an improved method for sampling CSF from mice. This improved technique collects mouse CSF samples with a 92% success rate and consistently yields relatively large volumes of CSF with a very low rate of blood contamination, as determined by molecular assessment of apolipoprotein B, a plasma-derived protein that is absent in the central nervous system. Through this improved method, we demonstrated that in mice receiving the administered apoE3 adenovirus, human apoE3 was expressed at high levels in the liver, leading to high levels of human apoE3 in mouse plasma. In contrast, human apoE3 levels in the CSF, as assessed by a sensitive ELISA, were essentially undetectable in human apoE3 adenovirus-treated mice, and comparable to levels in LacZ adenovirus-treated control mice. These data indicate that apoE in the CSF cannot be derived from the plasma pool and, therefore, must be synthesized locally in the brain.
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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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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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Badrnya, Sigrun, Tara Doherty, Ciaran Richardson, Robert I. McConnell, John V. Lamont, Michael Veitinger, Stephen P. FitzGerald, Maria Zellner, and Ellen Umlauf. "Development of a new biochip array for APOE4 classification from plasma samples using immunoassay-based methods." Clinical Chemistry and Laboratory Medicine (CCLM) 56, no. 5 (April 25, 2018): 796–802. http://dx.doi.org/10.1515/cclm-2017-0618.
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AbstractBackground:Apolipoprotein E (APOE) is a key player in lipid transport and metabolism and exists in three common isoforms: APOE2, APOE3 and APOE4. The presence of theE4allelic variant is recognized as a major genetic risk factor for dementia and other chronic (neuro)degenerative diseases. The availability of a validated assay for rapid and reliable APOE4 classification is therefore advantageous.Methods:Biochip array technology (BAT) was successfully applied to identify directly the APOE4 status from plasma within 3 h, through simultaneous immunoassay-based detection of both specific APOE4 and total APOE levels.Results:Samples (n=432) were first genotyped by polymerase chain reaction (PCR), and thereafter, using BAT, the corresponding plasma was identified as null, heterozygous or homozygous for theE4allele by calculating the ratio of APOE4 to total APOE protein. Two centers based in Austria and Ireland correctly classified 170 and 262 samples, respectively, and achieved 100% sensitivity and specificity.Conclusions:This chemiluminescent biochip-based sandwich immunoarray provides a novel platform to detect rapidly and accurately an individual’sAPOE4status directly from plasma. TheE4genotype of individuals has been shown previously to affect presymptomatic risk, prognosis and treatment response for a variety of diseases, including Alzheimer’s disease. The biochip’s potential for being incorporated in quantitative protein biomarker arrays capable of analyzing disease stages makes it a superior alternative to PCR-basedAPOEgenotyping and may deliver additional protein-specific information on a variety of diseases in the future.
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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.
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Huang, Yu-Wen Alvin, Bo Zhou, Marius Wernig, and Thomas C. Südhof. "ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion." Cell 168, no. 3 (January 2017): 427–41. http://dx.doi.org/10.1016/j.cell.2016.12.044.
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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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Hu, Monica L., Joel Quinn, and Kanmin Xue. "Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration." Life 11, no. 7 (June 29, 2021): 635. http://dx.doi.org/10.3390/life11070635.
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Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer’s disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.
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Raber, Jacob. "Role of Apolipoprotein E in Anxiety." Neural Plasticity 2007 (2007): 1–7. http://dx.doi.org/10.1155/2007/91236.
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Anxiety is most common among Alzheimer's disease (AD) patients with an age at onset under age 65. Apolipoprotein E4 (apoE4) is a risk factor for developing AD at an earlier age and might contribute to this effect. In mice, apoE plays a role in the regulation of anxiety, which might involve histamine receptor-mediated signaling and steroidogenesis in the adrenal gland. In addition, human apoE isoforms have differential effects on anxiety in adult mice lacking apoE and probable AD patients. Compared to wild-type mice, mice lacking apoE and apoE4 mice showed pathological alterations in the central nucleus of the amygdala, which is involved in regulation of anxiety. ApoE4, but not mice lacking apoE, or apoE3 mice showed impaired dexamethasone suppression of plasma corticosterone. Understanding how apoE modulates measures of anxiety might help the developments of therapeutic targets to reduce or even prevent measures of anxiety in health and in dementing illnesses.
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Wood, Kevin C. M., Morgan D. Fullerton, Ahmed El-Sohemy, and Marica Bakovic. "Interactions between hepatic lipase and apolipoprotein E gene polymorphisms affect serum lipid profiles of healthy Canadian adults." Applied Physiology, Nutrition, and Metabolism 33, no. 4 (August 2008): 761–68. http://dx.doi.org/10.1139/h08-054.
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The purpose of this study was to assess the individual and interactive effects between hepatic lipase (LIPC; C-514T, G-250A) and apolipoprotein E (APOE) (E2, E3, E4) gene polymorphisms on levels of plasma lipoprotein cholesterol and triglyceride among healthy, young, Canadian adults (n = 440). All subjects with at least one APOE2 allele had significantly lower low-density lipoprotein cholesterol, total cholesterol, and total cholesterol – high-density lipoprotein cholesterol ratio when compared with those with the APOE3 or APOE4 allele. There were significant differences in the LIPC allele and genotype frequencies between Caucasian (n = 207) and Asian (n = 211) individuals, but ethnicity did not contribute to the variations in circulating lipids. In addition, the lowest triglyceride levels (0.87 ± 0.27 mmol·mL–1) were found in all APOE2 individuals carrying LIPC-514-CC and LIPC-250-GG genotypes, whereas the highest triglyceride levels (1.29 ± 0.34 –1.32 ± 0.32 mmol·mL–1) were found in APOE2 individuals carrying the opposite genotypes, LIPC-514TT and LIPC-250AA. These observations, distinct from the anti-atherogenic effects of APOE2 through the lowering of low-density lipoprotein cholesterol and LIPC on high-density lipoprotein cholesterol, suggest that there is an interactive effect between APOE and LIPC genotypes on plasma triglyceride levels. These results provide the basis for further studies on establishing which genotype combinations would be the most protective against hypertriglyceridemia.
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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.