Apolipoprotein E and atherosclerosis

Apolipoprotein E plays a key protective role in atherosclerosis. Its capacity to safeguard against this disease can be attributed to at least three distinct functions. First, plasma apolipoprotein E maintains overall plasma cholesterol homeostasis by facilitating efficient hepatic uptake of lipoprotein remnants. Second, lesion apolipoprotein E in concert with apolipoprotein A-I facilitates cellular cholesterol efflux from macrophage foam cells within the intima of the lesion. Third, lesion apolipoprotein E directly modifies both macrophage- and T lymphocyte-mediated immune responses that contribute to this chronic inflammatory disease.     

Apolipoprotein E phenotypes and hyperlipidemia

Summary Apolipoprotein E phenotypes were determined in 361 patients with hyperlipidemia and in controls. The E2 isoform was significantly more frequent in the group of hyperlipidemics (P<0.0005). This was not due to a higher frequency of E-2/2 homozygotes with type III hyperlipoproteinemia, but rather to a significantly higher frequency of E2 heterozygotes (P<0.0005). Subgrouping of hyperlipidemics into patients with a) hypertriglyceridemia, b) hypercholesterolemia and c) mixed hyperlipidemia revealed i) that isoform E2 was significantly more frequent in patients with hypertriglyceridemia (0.001>P>0.005), ii) that isoform E4 was significantly more frequent in patients with hypercholesterolemia (0.01>P>0.005) and iii) that isoforms E2 (P>0.005) and E4 (0.05>P>0.025) were both more frequent in patients with mixed hyperlipidemia. Roughly 20% of patients with mixed hyperlipidemia had one of the rare phenotypes E-4/4,-4/2 or-2/2. We conclude that alleles 2 and 4 both contribute to the susceptibility for, and/or phenotypic expression of hyperlipidemia. Whereas the gene 2 seems to exert its influence on plasma lipoproteins by an abnormal gene product (E2) that has reduced binding activity to lipoprotein receptors, the mechanism underlying the association of the 4 gene with hyperlipidemia is presently unclear.     

Sulfation of Rat Apolipoprotein E

The synthesis of a 37-kilodalton (kDa) protein which has been shown recently to be identical with apolipoprotein E (apo-E) was increased after sciatic nerve injury of the rat. When regeneration of the nerve was allowed, its synthesis returned to control levels at about 8 weeks post injury. In this report it is shown that similar time-course studies of the protein in the rat optic nerve revealed a delayed increase of the protein but a comparably high level of synthesis at 3 weeks post injury. This level was maintained up to at least 18 weeks after crush. Furthermore, two-dimensional electrophoresis revealed that the characteristic "trailing" of the protein is due to its sialylation, because it was reduced after neuraminidase treatment. This treatment, however, detected a neuraminidase-resistant heterogeneous form in CNS tissue and a homogeneous form in peripheral nervous tissue. The trailing persisted up to 18 days of culture of optic nerve explants, of CNS glial cells, and of peritoneal macrophages, but disappeared during the first culture days of sciatic nerve explants and was not observed in Schwann cell culture media. Incorporation studies with 35SO4 revealed that apo-E was the major sulfated protein in culture media conditioned by CNS glial cells, whereas sulfation of the protein was undetectable in Schwann cell cultures. Because macrophages are likely to be the major source of apo-E in both peripheral and central glial cell cultures as well as in injured optic and sciatic nerves, it is hypothesized that resident cells of sciatic nerves secrete potent sulfatases. As a result, sialic acid residues may be more susceptible to degradation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Apolipoprotein E polymorphism in Saudis

Apolipoprotein E (apoE) genotypes were determined in 165 Saudis. The prevalence of genotype, E3/E3, E3/E4 and E4/E4 was found to be 71, 27 and 2% respectively. The E3/E3 was the most prevalent genotype among the Saudis followed by E3/E4. However, other genotypes E2/E2, E2/E3 and E2/E4 were absent showing the absence of E2 allele in the test population. The high frequencies of the E3 allele (0.845) and E3/E3 genotype (0.71) and absence of E2 allele in Saudis under study are similar to those reported earlier for Native Americans, Mexican-Americans, Mayans, Cayapa, Mazatecan Indians and Mexican Mestizos populations.     

Apolipoprotein E polymorphism in Saudis

Apolipoprotein E (apoE) genotypes were determined in 165 Saudis. The prevalence of genotype, E3/E3, E3/E4 and E4/E4 was found to be 71, 27 and 2% respectively. The E3/E3 was the most prevalent genotype among the Saudis followed by E3/E4. However, other genotypes E2/E2, E2/E3 and E2/E4 were absent showing the absence of E2 allele in the test population. The high frequencies of the E3 allele (0.845) and E3/E3 genotype (0.71) and absence of E2 allele in Saudis under study are similar to those reported earlier for Native Americans, Mexican-Americans, Mayans, Cayapa, Mazatecan Indians and Mexican Mestizos populations.     

Apolipoprotein E Polymorphism in Sheep

Using polyacrylamide gel isoelectric focusing followed by immunoblotting with anti-human apolipoprotein E (APO E) antibody, the genetic polymorphism of APO E was determined from desialylated plasma of 554 unrelated adults of four European sheep (Suffolk, Corriedale, Cheviot, and Finnish Landrace) and five Asian local sheep (Bhyanglung, Baruwal, Kagi, Lampuchhre, and Vietnamese). Twenty phenotypes consisting of the homozygous and heterozygous combinations of two APO E variants within the seven variants (E1-E7) detected were identified. Family and population data supported the hypothesis that the phenotypes are controlled by seven codominant alleles, designated APOE1 to APOE7, at a single autosomal locus. The common alleles, APOE4, APOE5, and APOE7 were observed at mean frequencies of 0.5763, 0.1471, and 0.1921 in the European sheep group and 0.4920, 0.1123, and 0.2995 in the Asian local sheep group, respectively.     

Apolipoprotein E phylogeny and evolution

Among apolipoproteins, apolipoprotein E (Apo E) plays a pivotal role in lipid transport and is proposed to be involved in neural repair. Because of a long divergence history of apolipoproteins, it is unclear how Apo E evolved in time. To investigate relationships among Apo E proteins, we used the information from molecular data and analysed the phylogeny of Apo E proteins from various species. Several phylogenetic trees were generated by using both character-based and distance-based phylogenetic methods. Apo E sequences of fish and frog were found to be less related to the Apo E sequences of other species. The most likely ancestor of Apo E among 18 organisms was estimated to be the Apo E of frog. Members of the groups formed by the Apo E proteins of various species shared similar feeding habits and diet. It may be suggested that Apo E evolution and very likely the evolution of other apolipoproteins are influenced by the organism's feeding environment and diet.     

载脂蛋白E与癫痫的关系

载脂蛋白E（apolipoprotein E,ApoE）在中枢神经系统修复受损细胞膜、轴索生长和突触形成的过程中起重要作用.研究证明,在外伤、中毒、免疫应答以及痫性放电引起的脑部损伤的病灶组织中都存在载脂蛋白E表达的上调现象.载脂蛋白E的基因多态性和表达量与难治性癫痫的发生和发展有一定的相关性,提示载脂蛋白E的异常可能是难治性癫痫产生机制中的一个重要环节.     

Apolipoprotein E metabolism in normolipoproteinemic human subjects

Human apolipoprotein E (apoE) is a constituent of plasma very low density and high density lipoproteins and is important in modulating the catabolism of remnants of triglyceride-rich lipoproteins. There are three common isoforms of apoE, designated apoE-2, E-3, and E-4, which are coded by three separate alleles (epsilon 2, epsilon 3, and epsilon 4) at a single genetic locus and inherited in the population in a co-dominant fashion. ApoE-3 is the predominant apoE isoform in the normolipidemic population, and epsilon 3 has been proposed to be the normal allele. ApoE-3 metabolism was studied in nine normolipidemic subjects homozygous for the epsilon 3 allele. In these subjects, the plasma apoE-3 concentration was 4.8 +/- 1.2 mg/dl (mean +/- SD), the plasma apoE-3 residence time was 0.73 +/- 0.18 days, and the plasma apoE-3 production rate was 3.4 +/- 1.5 mg/kg-day. The apoE in males, when compared to females, tended to have a shorter residence time (0.63 +/- 0.15 days versus 0.83 +/- 0.16), a higher production rate (4.20 +/- 1.73 mg/kg-days versus 2.60 +/- 0.78), but a similar plasma concentration (5.1 +/- 1.5 mg/dl versus 4.5 +/- 0.8). ApoE-3 had a more rapid catabolism from plasma than other apolipoproteins previously studied (apolipoproteins A-I, A-II, A-IV, B-100, C-II, and C-III) except for apolipoprotein B-48. The catabolism of apoE-3 in the individual lipoprotein subfractions was also examined and apoE was shown to be catabolized most rapidly from the VLDL and slowest from the HDL. The results of the kinetic analysis of apoE metabolism are consistent with apoE being important in the catabolism of triglyceride-rich lipoproteins and with HDL serving as a reservoir for apoE to reassociate with newly secreted triglyceride-rich lipoproteins.     

载脂蛋白E基因多态性与阿尔茨海默病

利用PCR RFLP方法分析了中国汉族人群中 16 0例散发性阿尔茨海默病 (Alzheimerdisease,AD)患者和 195例正常对照老年人中载脂蛋白E(APOE)基因多态性分布的差异。结果表明 ,APOE 3种等位基因ε2、ε3和ε4的频率在AD组和对照组分别为 0 0 5 6、0 713、0 2 31和 0 0 82、0 84 4、0 0 74。APOEε4等位基因携带个体患AD的危险为非携带个体的 3 82倍 (χ2 =2 8 7,P <0 0 0 1)。 6 5岁以上APOEε4携带个体患AD的危险为非携带个体的 5 38倍(χ2 =2 9 8,P <0 0 0 1) ,说明年龄因素可能影响ε4与AD间的相互作用。APOE等位基因和基因型频率在轻、中和重度痴呆病人间的分布无明显差异 (P >0 0 5 ) ,提示APOE基因多态性可能与AD患者的痴呆程度无关联。APOEε4基因型频率在女性AD病人中的分布略高于男性AD病人 (4 3 0 %对 36 5 % ) ,女性ε4携带个体患AD的危险也高于男性ε4携带个体 (4 3倍对 3 3倍 ) ,但统计学分析未检测到这些差异的显著性 (P >0 0 5 )。ε2等位基因频率在AD患者男性亚组明显低于女性亚组 ,也低于对照人群的男性亚组 (P <0 0 5 ) ,提示ε2等位基因可能降低中国汉族男性人群AD发病的危险     

Apolipoprotein E structure: insights into function

Human apolipoprotein E (apoE) is a member of the family of soluble apolipoproteins. Through its interaction with members of the low-density lipoprotein receptor family, apoE has a key role in lipid transport both in the plasma and in the central nervous system. Its three common structural isoforms differentially affect the risk of developing atherosclerosis and neurodegenerative disorders, including Alzheimer's disease. Because the function of apoE is dictated by its structure, understanding the structural properties of apoE and its isoforms is required both to determine its role in disease and for the development of therapeutic strategies.     

Apolipoprotein E phenotypes in patients with myocardial infarction

Summary The frequencies of genetic apo E isoforms E2, E3 and E4 were determined in 523 patients with myocardial infarction and compared to those in a control group (1031 blood donors). A significant difference in the frequency of apo E4 was noted between patients and controls (0.05> P>0.025). No differences in the frequencies of isoforms E3 and E2 were observed. In particular, there was no significant difference between the two groups in the frequency of apo E2 homozygosity. a condition that is associated with type III hyperlipoproteinemia. However, all E2 homozygote survivors of myocardial infarction had hyperlipoproteinemia type III (cholesterol 269±29 mg/dl; triglyceride 419±150 mg/dl; age 54±14 years; N=5). On the contrary, E2 homozygote controls (all apo E-2/2 blood donors and their apo E-2/2 relatives who were from the same age range as the patients) had primary dysbetalipoproteinemia but normal or subnormal plasma cholesterol concentrations (cholesterol 184±28 mg/dl; triglyceride 151±52 mg/dl; age 56±13 years; N=11). This indicates that E2 homozygotes with hyperlipoproteinemia type III who occur rarely in the population but comprise about 1% of myocardial infarction patients have a markedly increase risk for coronary atherosclerosis, whereas the risk for E2 homozygotes with normal or subnormal plasma cholesterol (=primary dysbetalipoproteinemia) may be considerably lower than for the general population. The data illustrate the complex relationship between apo E genes, lipid levels, and risk for atherosclerosis.     

Apolipoprotein E isoprotein-specific interactions with tissue plasminogen activator

Apolipoprotein E (Apo E) is an important genetic risk factor for multiple neurological, vascular and cardiovascular diseases. Previously, we reported Apo E isoprotein-specific modulation of tissue plasminogen activator (tPA) using an in vitro blood-clotting assay. Here, we studied the conformational changes of Apo E2, E3 and E4 in the presence of tPA and vice versa using circular dichroism (CD) and dual polarization interferometry (DPI). We report isoprotein and state-specific intermolecular interactions between the Apo E isoforms and tPA. Apo E2 interaction with immobilized tPA leads to significant conformational changes which are not observed with Apo E3 or E4. Additionally, tPA induces changes in helicity of lipidated Apo E2 whereas no detectable changes were observed in Apo E3 or E4. The Tukey's test for interaction indicated a significant (P < 0.001) interaction between tPA and Apo E2 in the lipidated environment. These results may be important regarding the mechanism by which Apo E has isoprotein-specific effects on many biological processes and diseases involving blood clotting, proteolysis and perfusion.     

Apolipoprotein E, amyloid, and Alzheimer disease

Despite important inroads into the molecular pathology of Alzheimer disease, effective long-term treatment for the condition remains elusive. Among the many gene products that are recognized as factors in the disease is apolipoprotein ( (apoE). The risk that specific isoforms of apoE pose with regard to Alzheimer Disease clearly varies, and so the roles that apoE plays in the brain will be crucial to a full understanding of the disease and to efforts to develop effective therapies.     

Apolipoprotein E genotyping among the healthy Kuwaiti population

Apolipoproteins (lipid-free) are lipid-binding proteins that circulate in the plasma of human blood and are responsible for the clearance of lipoproteins. Apolipoprotein E (ApoE) is one of the several classes of this protein family. It acts as a ligand for the low-density lipid (LDL) receptors and is important for the clearance of very low-density lipid (VLDL) and chylomicron remnants. The APOE gene locus is polymorphic, with three major known alleles, APOE*3, *4, and *2. We investigated the distribution of the allele frequency of the APOE gene locus and describe here the genetic variation in four Kuwaiti subpopulations: Arab origin (Arabian peninsula), Arab Bedouin tribes, Iranian origin, and the heterogeneous population. We also describe the use of Spreadex gels in resolving the amplified and digested products of the APOE gene locus. DNA was extracted from whole blood and subjected to PCR and then to RFLP analysis. Allele and genotype frequencies were estimated for the total population and for each subpopulation. Statistical analysis showed no difference in the allele frequencies between the four groups. The frequency of APOE*3 in the Kuwaiti population was highest (88.4%) followed by the frequency of APOE*4 (6.5%) and APOE*2 (5.1%). The genotype and allele frequencies obtained for the Kuwaiti population fell within the reported worldwide distribution for the APOE gene locus. Moreover, the results obtained in this study showed no statistical difference (p > 0.05) between the APOE allele and genotype frequencies between the subgroups for all six genotypes and three alleles, supporting the assumption of admixture in the Kuwaiti population and that the obtained frequencies were in Hardy-Weinberg equilibrium. Finally, we found that the distribution of the APOE alleles in Kuwait differs somewhat from those reported in other Arab populations, suggesting that the Arabs originating from the Arabian peninsula are different from those of Lebanon, Morocco, and Sudan.     

Apolipoprotein E gene polymorphisms in Lebanese with hypercholesterolemia

Apolipoprotein E (ApoE) has an important role in the metabolism of lipids through its major isoforms (ε2, ε3, ε4). In particular, ApoE ε4, has been considered as a major genetic risk factor for cardiovascular diseases (CVD). The aim of our study is to investigate the frequency of ApoE gene polymorphisms (rs 429358C > T, rs 7412C > T) and their relationship to lipid parameters in a group of Lebanese hypercholesterolemic subjects (22 males and 24 females, aged 25–80 years). Lipid profile, apolipoproteins A-I and B were determined using fasting serum samples; and molecular analysis of ApoE polymorphisms using blood in EDTA tubes. The distribution of the four ApoE genotypes detected in this study was: ε3/ε3 (73.9%), ε3/ε4 (17.4%), ε2/ε3 (6.5%), and ε2/ε4 (2.2%) resulting in allelic frequencies for ε2, ε3 and ε4 of 4.3%, 85.9% and 9.8%, respectively. No association was determined among any of the lipid parameters, gender and ApoE genotypes. Lipid parameters were not statistically different among various ApoE genotypes (p > 0.05). ApoE ε2 frequency was found to be lower than that previously reported for healthy Lebanese (7.2%). CVD is one of the major leading causes of mortality in Lebanon with a reported prevalence of 12.2% in males and 7.7% in females, which incidentally agrees with our finding regarding ε4 allelic frequency of 13.6% in males and 6.3% in females. Consequently, larger prospective studies are recommended to highlight the correlation of ApoE polymorphisms to other biochemical and environmental factors involved in CVD.     

Apolipoprotein E modulates the CNS response to injury

Apolipoprotein E (apoE) plays an important role in recovery from acute brain injury. One potential mechanism for this is that apoE down‐regulates glial activation and subsequent secretion of inflammatory mediators. Following a pneumatic impact to the closed skull of anesthetized apoE deficient and wildtype mice, MRI was performed to quantify the effacement of the lateral ventricles as a radiographic surrogate for cerebral edema. At 24 hours following injury, apoE deficient animals had a greater degree of cerebral edema as compared to matched controls. This increase in edema was associated with enhanced up‐regulation of TNFα, a pro‐inflammatory cytokine believed to play an important role in mediating blood–brain barrier breakdown and the development of cerebral edema. We have previously demonstrated that a peptide derived from the receptor binding region of apoE retained the anti‐inflammatory activities of the holoprotein in vitro, and we next investigated whether a single intravenous administration of this apoE‐mimetic peptide could exert neuroprotective effects. Thirty minutes after closed head injury, mice were randomized to receive low dose peptide (203 mg/kg); high dose peptide (406 mg/kg), or vehicle. At 24 h post injury, the saline injected animals had a profound deficit in rotorod testing which was associated with weight loss. A single intravenous injection of apoE‐mimetic peptide 30 min following closed head injury protected against motor deficit, weight loss, and neurocognitive deficit in a dose dependent fashion. This suggests that apoE may modify prognosis in brain injury by down‐regulating the CNS inflammatory response, and that mimicking the biological activity of apoE may lead to novel therapeutic strategies in the setting.     

Apolipoprotein E region molecular signatures of Alzheimer's disease

Although the APOE region is the strongest genetic risk factor for Alzheimer's diseases (ADs), its pathogenic role remains poorly understood. Elucidating genetic predisposition to ADs, a subset of age‐related diseases characteristic for postreproductive period, is hampered by the undefined role of evolution in establishing molecular mechanisms of such diseases. This uncertainty is inevitable source of natural‐selection–free genetic heterogeneity in predisposition to ADs. We performed first large‐scale analysis of linkage disequilibrium (LD) structures characterized by 30 polymorphisms from five genes in the APOE 19q13.3 region (BCAM, NECTIN2, TOMM40, APOE, and APOC1) in 2,673 AD‐affected and 16,246 unaffected individuals from five cohorts. Consistent with the undefined role of evolution in age‐related diseases, we found that these structures, being highly heterogeneous, are significantly different in subjects with and without ADs. The pattern of the difference represents molecular signature of AD comprised of single nucleotide polymorphisms (SNPs) from all five genes in the APOE region. Significant differences in LD in subjects with and without ADs indicate SNPs from different genes likely involved in AD pathogenesis. Significant and highly heterogeneous molecular signatures of ADs provide unprecedented insight into complex polygenetic predisposition to ADs in the APOE region. These findings are more consistent with a complex haplotype than with a single genetic variant origin of ADs in this region.     

Apolipoprotein E: From lipid transport to neurobiology

Apolipoprotein (apo) E has a storied history as a lipid transport protein. The integral association between cholesterol homeostasis and lipoprotein clearance from circulation are intimately related to apoE’s function as a ligand for cell-surface receptors of the low-density lipoprotein receptor family. The receptor binding properties of apoE are strongly influenced by isoform specific amino acid differences as well as the lipidation state of the protein. As understanding of apoE as a structural component of circulating plasma lipoproteins has evolved, exciting developments in neurobiology have revitalized interest in apoE. The strong and enduring correlation between the apoE4 isoform and age of onset and increased risk of Alzheimer’s disease has catapulted apoE to the forefront of neurobiology. Using genetic tools generated for study of apoE lipoprotein metabolism, transgenic “knock-in” and gene-disrupted mice are now favored models for study of its role in a variety of neurodegenerative diseases. Key structural knowledge of apoE and isoform-specific differences is driving research activity designed to elucidate how a single amino acid change can manifest such profoundly significant pathological consequences. This review describes apoE through a lens of structure-based knowledge that leads to hypotheses that attempt to explain the functions of apoE and isoform-specific effects relating to disease mechanism.