Apolipoprotein E

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Apolipoprotein E (ApoE) is a class of proteins involved in the metabolism of fats in the body. It is important in Alzheimer's disease and cardiovascular disease.[1]

Lipoproteins are molecules composed of fats and proteins. Apolipoprotein E is a fat-binding protein (apolipoprotein) that is part of the chylomicron and intermediate-density lipoprotein (IDLs). These are essential for the normal processing (catabolism) of triglyceride-rich lipoproteins.[2] In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, ApoE is mainly produced by astrocytes and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family.[3] ApoE is the principal cholesterol carrier in the brain.[4]

Structure

Gene

The gene, APOE, is mapped to chromosome 19 in a cluster with apolipoprotein C1 (APOC-I) and the apolipoprotein C2. The APOE gene consists of four exons and three introns, totaling 3597 base pairs. APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucose homeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors.[5] In melanocytic cells APOE gene expression may be regulated by MITF.[6]

Protein

APOE is 299 amino acids long and contains multiple amphipathic α-helices. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposed hydrophobic surface and interact with those in the N-terminal helix bundle domain through hydrogen bonds and salt-bridges. The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site.[7]

Polymorphisms

SNP: Apolipoprotein E
GeneApoE
Chromosome19
External databases
EnsemblHuman SNPView
dbSNP429358
HapMap429358
SNPedia429358

APOE is polymorphic,[8][9] with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158).[1][10][11] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,[12][13][14] these differences alter APOE structure and function. These have physiological consequences:

However, there is much to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimer’s Disease. In addition, there is no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease.[37]

Function

APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen.[10] In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.[38] There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.[39]

APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL remnants.[2] More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition.[1] Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.[40]

In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1) [41] to natural killer T cell as well as modulation of inflammation and oxidation.[42] APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.[43]

Clinical significance

Alzheimer's disease

The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.[44] However, the E4 variant does not correlate with risk in every population. Nigerian blacks have the highest observed frequency of the APO E*4 allele in world populations,[45] but AD is rare among them.[45][46] This may be due to their low cholesterol levels.[45][46][47][48] Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with amyloid.[49] Alzheimer's disease is characterized by build-ups of aggregates of the peptide beta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform ApoE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.[50]

Although 40–65% of AD patients have at least one copy of the ε4 allele, ApoE4 is not a determinant of the disease – at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.[51] There is also evidence that the ApoE2 allele may serve a protective role in AD.[52] Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4. Using genotype ApoE 3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype ApoE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the ApoE 3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (ApoE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (ApoE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (ApoE2,2) also have an odds ratio of 0.6.[53]

Estimated worldwide human allele frequencies of ApoE * in Caucasian population[53]
Allele ε2 ε3 ε4
General Frequency 8.4% 77.9% 13.7%
AD Frequency 3.9% 59.4% 36.7%

While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer’s, a 2002 study concluded, that in persons with any combination of ApoE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.[48] Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person’s risk for Alzheimer’s disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.[48]

Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.[54]

Atherosclerosis

Knockout mice that lack the apolipoprotein-E gene (ApoE−/−) develop extreme hypercholesterolemia when fed a high-fat diet.[55]

Malaria

ApoE−/− knockout mice show marked attenuation of cerebral malaria and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the blood-brain barrier.[56] Human studies have shown that the ApoE2 polymorphism correlates with earlier infection and ApoE3/4 polymorphisms increase likelihood of severe malaria.[57]

Interactions

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin Pathway edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Evolution

Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them.[58] Proteins similar in function have been found in choanoflagellates, suggesting that they are a very old class of proteins predating the dawn of all living animals. It is believed that the APOE arose via gene duplications of APOC-I before the fish-mammal split 400 million years ago.[59]

The three major human alleles (E4, E3, E2) arose after the primate-human split around 7.5 million years ago. These alleles are the by-product of non-synonymous mutations which led to changes in functionality. The first allele to emerge was E4. After the primate-human split there were four amino acid changes in the human lineage, three of those changes had no effect (V174L, A18T, A135V), but the fourth substitution traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate-human split and the Denisovan-human split, since the exact same substitutions were found in Denisovan APOE.[60]

About 220,000 years ago, an arginine to cysteine substitution took place at amino acid 112 (Arg112Cys) of the APOE4 gene and this resulted in the E3 allele. Finally, 80,000 years ago another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele.[61][59]

References

  1. ↑ 1.0 1.1 1.2 Stolerman IP, ed. (2010). Encyclopedia of Psychopharmacology (Online ed.). Berlin: Springer. ISBN 978-3540686989.
  2. ↑ 2.0 2.1 "Entrez Gene: APOE apolipoprotein E".
  3. ↑ Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (February 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology. 9 (2): 106–18. doi:10.1038/nrneurol.2012.263. PMC 3726719. PMID 23296339.
  4. ↑ Puglielli L, Tanzi RE, Kovacs DM (April 2003). "Alzheimer's disease: the cholesterol connection". Nature Neuroscience. 6 (4): 345–51. doi:10.1038/nn0403-345. PMID 12658281.
  5. ↑ Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P (January 2001). "A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis". Molecular Cell. 7 (1): 161–71. doi:10.1016/S1097-2765(01)00164-2. PMID 11172721.
  6. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
  7. ↑ Phillips MC (September 2014). "Apolipoprotein E isoforms and lipoprotein metabolism". IUBMB Life. 66 (9): 616–23. doi:10.1002/iub.1314. PMID 25328986.
  8. ↑ Singh PP, Singh M, Mastana SS (2006). "APOE distribution in world populations with new data from India and the UK". Annals of Human Biology. 33 (3): 279–308. doi:10.1080/03014460600594513. PMID 17092867.
  9. ↑ Eisenberg DT, Kuzawa CW, Hayes MG (September 2010). "Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history". American Journal of Physical Anthropology. 143 (1): 100–11. doi:10.1002/ajpa.21298. PMID 20734437.
  10. ↑ 10.0 10.1 Baars HF, van der Smagt JJ, Doevandans P (2011). Clinical Cardiogenetics. London: Springer. ISBN 978-1849964715.
  11. ↑ Ghebranious N, Ivacic L, Mallum J, Dokken C (2005). "Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology". Nucleic Acids Research. 33 (17): e149. doi:10.1093/nar/gni155. PMC 1243648. PMID 16204452.
  12. ↑ Online Mendelian Inheritance in Man (OMIM) APOE3 isoform, hyperlipoproteinemia, type III, autosomal recessive -107741#0015
  13. ↑ Online Mendelian Inheritance in Man (OMIM) APOE3 isoform, APOE, CYS112 and ARG158 -107741#0001
  14. ↑ Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J (2006). "Variation at APOE and STH loci and Alzheimer's disease". Behavioral and Brain Functions. 2 (1): 13. doi:10.1186/1744-9081-2-13. PMC 1526745. PMID 16603077.
  15. ↑ 15.0 15.1 15.2 "Alzheimer Research Forum: Meta-Analyses of apolipoprotein E AD Association Studies". Archived from the original on 2012-11-24.
  16. ↑ Weisgraber KH, Innerarity TL, Mahley RW (March 1982). "Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site". The Journal of Biological Chemistry. 257 (5): 2518–21. PMID 6277903.
  17. ↑ Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ (November 1982). "Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2". Journal of Lipid Research. 23 (8): 1224–35. PMID 7175379.
  18. ↑ Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W (1998). "Molecular basis of type III hyperlipoproteinemia in Germany". Human Mutation. 11 (6): 417–23. doi:10.1002/(SICI)1098-1004(1998)11:6<417::AID-HUMU1>3.0.CO;2-5. PMID 9603433.
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  23. ↑ Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (August 1993). "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families". Science. 261 (5123): 921–23. doi:10.1126/science.8346443. PMID 8346443.
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  27. ↑ Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK (June 2008). "Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression". Proceedings of the National Academy of Sciences of the United States of America. 105 (25): 8718–23. doi:10.1073/pnas.0803526105. PMC 2438419. PMID 18562290.
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  32. ↑ Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM, Mignot E (June 2001). "Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults". JAMA. 285 (22): 2888–90. doi:10.1001/jama.285.22.2888. PMID 11401610.
  33. ↑ Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T (August 2004). "APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study". Neurology. 63 (4): 664–68. doi:10.1212/01.wnl.0000134671.99649.32. PMID 15326239.
  34. ↑ Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL (February 2013). "Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use". PLOS One. 8 (2): e54713. doi:10.1371/journal.pone.0054713. PMC 3572118. PMID 23418430.
  35. ↑ Raber J (May 2008). "AR, apoE, and cognitive function". Hormones and Behavior. 53 (5): 706–15. doi:10.1016/j.yhbeh.2008.02.012. PMC 2409114. PMID 18395206.
  36. ↑ Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Müller MJ, Schreiber S, Nöthlings U, Rimbach G (September 2011). "APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans". FASEB Journal. 25 (9): 3262–70. doi:10.1096/fj.11-180935. PMID 21659554.
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  45. ↑ 45.0 45.1 45.2 Sepehrnia B, Kamboh MI, Adams-Campbell LL, Bunker CH, Nwankwo M, Majumder PP, Ferrell RE (October 1989). "Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks". American Journal of Human Genetics. 45 (4): 586–91. PMC 1683508. PMID 2491016.
  46. ↑ 46.0 46.1 Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J, Nissinen A (1998-01-01). "Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease". Neuroepidemiology. 17 (1): 14–20. doi:10.1159/000026149. PMID 9549720.
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  48. ↑ 48.0 48.1 48.2 Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H (August 2002). "Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease". Annals of Internal Medicine. 137 (3): 149–55. doi:10.7326/0003-4819-137-3-200208060-00006. PMID 12160362.
  49. ↑ Wisniewski T, Frangione B (February 1992). "Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid". Neuroscience Letters. 135 (2): 235–38. doi:10.1016/0304-3940(92)90444-C. PMID 1625800.
  50. ↑ Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE (June 2008). "ApoE promotes the proteolytic degradation of Abeta". Neuron. Cell Press. 58 (5): 681–93. doi:10.1016/j.neuron.2008.04.010. PMC 2493297. PMID 18549781. Lay summary – ScienceDaily (2008-06-13).
  51. ↑ Hauser PS, Ryan RO (October 2013). "Impact of apolipoprotein E on Alzheimer's disease". Current Alzheimer Research. 10 (8): 809–17. doi:10.2174/15672050113109990156. PMC 3995977. PMID 23919769.
  52. ↑ Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE (June 1994). "Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease". Nature Genetics. 7 (2): 180–84. doi:10.1038/ng0694-180. PMID 7920638.
  53. ↑ 53.0 53.1 Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM (1997). "Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium". JAMA. 278 (16): 1349–56. doi:10.1001/jama.1997.03550160069041. PMID 9343467.
  54. ↑ Damoiseaux, Jessica S.; Seeley, William W.; Zhou, Juan; Shirer, William R.; Coppola, Giovanni; Karydas, Anna; Rosen, Howard J.; Miller, Bruce L.; Kramer, Joel H. (2012-06-13). "Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels". Journal of Neuroscience. 32 (24): 8254–62. doi:10.1523/JNEUROSCI.0305-12.2012. ISSN 0270-6474. PMC 3394933. PMID 22699906.
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Further reading

External links

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