Understanding the Brain

Apolipoprotein E

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Apolipoprotein E (APOE) is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.[1]

Function

APOE[2] is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. 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.

In the field of immune regulation, a growing amount 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) to natural killer T cell as well as modulation of inflammation and oxidation.[3]

Neonates with brain injuries and/or defects who also have abnormalities in the APOE gene may have an increased risk for cerebral palsy, according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL remnants.

APOE is 299 amino acids long and transports lipoproteins, 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. 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. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved low density lipoprotein receptor gene family.

Gene

The protein, ApoE, is mapped to chromosome 19 in a cluster with Apolipoprotein C1 and the Apolipoprotein C2. The APOE gene consists of four exons and three introns, totaling 3597 base pairs. In melanocytic cells APOE gene expression may be regulated by MITF.[4]

ApoE is polymorphic[5][6] with three major isoforms, ApoE2, ApoE3, ApoE4, which translate into three alleles of the gene:

  • Normal: ApoE-ε3
  • Dysfunctional: ApoE-ε2 and ApoE-ε4

These allelic forms differ from each other only by amino acid substitutions at positions 112 and 158.[7].On Entrez SNP these are positions 130 and 176, rs429358 and rs7412 respectively; Entrez SNP positioning and positioning within Ensembl Genome Browser as 130 and 176 being those of the preprotein, intracellular proteolysis shifting these to positions 112 and 158. The E2 allele has a Cys at positions 112 and 158 in the receptor-binding region of ApoE. The E3 allele is Cys-112 and Arg-158. The ApoE E4 allele is Arg at both positions.[8] These have physiological consequences:

  • E2 is associated with the genetic disorder hyperlipoproteinemia type III and with both increased and decreased risk for atherosclerosis. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and type III hyperlipoproteinemia—94.4% of such patients are E2/E2, while only ∼2% of E2/E2 develop the disease. So other environmental and genetic factors are likely to be involved.[9][10][11]
  • E3 is found in approximately 64 percent of the population. It is considered the "neutral" Apo E genotype.

ApoE is a target gene of the liver X receptor, a nuclear receptor member that plays a role in the metabolism regulation of cholesterol, fatty acid, and glucose homeostasis.

Estimated worldwide human allele frequencies of ApoE based upon over 200 world populations and 50,000 people (highly variable depending upon population)*[6]
Allele ε2 ε3 ε4
Frequency 0 - 37.5% 8.5 - 98.0% 0 - 49%

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. 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. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid (insoluble protein aggregates). 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. Some isoforms of ApoE are not as efficient as others at catalyzing these reactions. In particular, the isoform ApoE-ε4 is not very effective, resulting in increased vulnerability to Alzheimer's in individuals with that gene variation.[12]

The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance[13] while working in the Roses lab at Duke University[14] Linkage studies were followed by association analysis confirming the role of the ApoE4 allele.[15]

Although 40-65% of AD patients have at least one copy of the 4 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 e4 alleles have up to 20 times the risk of developing AD. There is also evidence that the ApoE2 allele may serve a protective role in AD.[16] Thus, the genotype most at risk for Alzheimer's disease and at earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer's disease. The genotype ApoE 2,3 is considered at less risk for Alzheimer's disease. Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk similar to the ApoE 3,3 genotype.

The connection between neuron failure in Alzheimer's disease and depleted myelin cholesterol (via ApoE deficiency) has also been described in Cholesterol Depletion and consequently is a known statin therapy adverse drug reaction.[17][18][19][20][21]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.[22]

References

  1. "Entrez Gene: APOE apolipoprotein E". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348. 
  2. Singh PP, Singh M, Mastana SS (2002). "Genetic variation of apolipoproteins in North Indians". Hum. Biol. 74 (5): 673–82. doi:10.1353/hub.2002.0057. PMID 12495081. 
  3. Zhang HL, Wu J, Zhu J (2010). "The role of apolipoprotein e in guillain-barré syndrome and experimental autoimmune neuritis". J. Biomed. Biotechnol. 2010: 357412. doi:10.1155/2010/357412. PMC 2825561. PMID 20182542. 
  4. Hoek KS, Schlegel NC, Eichhoff OM, et al. (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. 
  5. Singh PP, Singh M, Mastana SS (2006). "APOE distribution in world populations with new data from India and the UK.". Ann.Hum. Biol. 33 (3): 279–308. doi:10.1080/03014460600594513. PMID 17092867. 
  6. 6.0 6.1 Eisenberg DTA, Kuzawa CW, Hayes MG. (2010). "Worldwide allele frequencies of the human apoliprotein E (APOE) gene: climate, local adaptations and evolutionary history". American Journal of Physical Anthropology 143 (1): 100–111. doi:10.1002/ajpa.21298. 
  7. Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J (2006). "Variation at APOE and STH loci and Alzheimer's disease". Behav Brain Funct 2: 13. doi:10.1186/1744-9081-2-13. PMC 1526745. PMID 16603077. 
  8. Ghebranious N, Ivacic L, Mallum J, and Dokken C (2005). "Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology". Nucleic Acids Res. 33: e149. PMC 1243648. PMID 16204452. 
  9. Breslow J.L., Zannis V.I., SanGiacomo T.R., Third J.L., Tracy T., Glueck C.J. (1982). "Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2". J. Lipid Res. 23 (8): 1224–1235. PMID 7175379. 
  10. Feussner G., Feussner V., Hoffmann M.M., Lohrmann J., Wieland H., Marz W. (1998). "Molecular basis of type III hyperlipoproteinemia in Germany". Hum. Mutat. 11 (6): 417–423. doi:10.1002/(SICI)1098-1004(1998)11:6<417::AID-HUMU1>3.0.CO;2-5. PMID 9603433. 
  11. Civeira F., Pocovi M., Cenarro A., Casao E., Vilella E., Joven J., Gonzalez J., Garcia-Otin A.L., Ordovas J.M. Apo E variants in patients with type III hyperlipoproteinemia. (1996). "Apo E variants in patients with type III hyperlipoproteinemia.". Atherosclerosis 127 (2): 273–282. doi:10.1016/S0021-9150(96)05969-2. PMID 9125318. 
  12. 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 (2008-06-12). "ApoE promotes the proteolytic degradation of Abeta". Neuron (United States: Cell Press) 58 (5): 681–93. doi:10.1016/j.neuron.2008.04.010. PMC 2493297. PMID 18549781. Lay summary – ScienceDaily (2008-06-13). 
  13. "Margaret Pericak-Vance, Ph.D.". Miami Institute of Human Genomics. http://www.mihg.org/weblog/people/2007/11/margaret-pericakvance-phd.html. 
  14. Pericak-Vance MA, Bebout JL, Gaskell PC Jr, Yamaoka LH, Hung W-Y, Alberts MJ, Walker AP, Bartlett RJ, Haynes CA, Welsh KA, Earl NL, Heyman A, Clark CM, and Roses AD (1991). "Linkage studies in familial Alzheimer disease: Evidence for chromosome 19 linkage". Am J Hum Genet 48 (6): 1034–50. PMC 1683100. PMID 2035524. 
  15. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993). "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families". Science 261 (5123): 921–3. doi:10.1126/science.8346443. PMID 8346443. 
  16. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE (1994). "Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease". Nat. Genet. 7 (2): 180–4. doi:10.1038/ng0694-180. PMID 7920638. 
  17. Mason RP, Shoemaker WJ, Shajenko L, Chambers TE, Herbette LG (1992). "Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol". Neurobiol. Aging 13 (3): 413–9. doi:10.1016/0197-4580(92)90116-F. PMID 1625771. 
  18. Eckert GP, Kirsch C, Leutz S, Wood WG, Müller WE (September 2003). "Cholesterol modulates amyloid beta-peptide's membrane interactions". Pharmacopsychiatry 36 Suppl 2: S136–43. doi:10.1055/s-2003-43059. PMID 14574628. 
  19. Howland DS, Trusko SP, Savage MJ, Reaume AG, Lang DM, Hirsch JD, Maeda N, Siman R, Greenberg BD, Scott RW, Flood DG (June 1998). "Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol". J. Biol. Chem. 273 (26): 16576–82. doi:10.1074/jbc.273.26.16576. PMID 9632729. 
  20. Lepara O, Valjevac A, Alajbegović A, Zaćiragić A, Nakas-Ićindić E (August 2009). "Decreased serum lipids in patients with probable Alzheimer's disease". Bosn J Basic Med Sci 9 (3): 215–20. PMID 19754476. 
  21. Golomb BA, Evans MA (2008). "Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism". Am J Cardiovasc Drugs 8 (6): 373–418. doi:10.2165/0129784-200808060-00004. PMC 2849981. PMID 19159124. 
  22. The interactive pathway map can be edited at WikiPathways: "StatinPathway_WP430". http://www.wikipathways.org/index.php/Pathway:WP430. 

Further reading

  • Gunzburg MJ, Perugini MA, Howlett GJ. (2007). "Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E.". J. Biol. Chem. 282 (49): 35831–41. doi:10.1074/jbc.M706425200. PMID 17916554. 
  • Mahley RW (1988). "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.". Science 240 (4852): 622–30. doi:10.1126/science.3283935. PMID 3283935. 
  • Strittmatter WJ, Roses AD (1995). "Apolipoprotein E and Alzheimer disease.". Proc. Natl. Acad. Sci. U.S.A. 92 (11): 4725–7. doi:10.1073/pnas.92.11.4725. PMC 41779. PMID 7761390. 
  • de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM (1995). "Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels.". Hum. Mutat. 4 (3): 178–94. doi:10.1002/humu.1380040303. PMID 7833947. 
  • Roses AD, Einstein G, Gilbert J, et al. (1996). "Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism.". Ann. N. Y. Acad. Sci. 777: 146–57. doi:10.1111/j.1749-6632.1996.tb34413.x. PMID 8624078. 
  • Beffert U, Danik M, Krzywkowski P, et al. (1998). "The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease.". Brain Res. Brain Res. Rev. 27 (2): 119–42. doi:10.1016/S0165-0173(98)00008-3. PMID 9622609. 
  • Mahley RW, Ji ZS (1999). "Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E.". J. Lipid Res. 40 (1): 1–16. PMID 9869645. 
  • Mahley RW, Rall SC (2002). "Apolipoprotein E: far more than a lipid transport protein.". Annual review of genomics and human genetics 1: 507–37. doi:10.1146/annurev.genom.1.1.507. PMID 11701639. 
  • Parasuraman R, Greenwood PM, Sunderland T (2002). "The apolipoprotein E gene, attention, and brain function.". Neuropsychology 16 (2): 254–74. doi:10.1037/0894-4105.16.2.254. PMC 1350934. PMID 11949718. 
  • Bocksch L, Stephens T, Lucas A, Singh B (2003). "Apolipoprotein E: possible therapeutic target for atherosclerosis.". Current drug targets. Cardiovascular & haematological disorders 1 (2): 93–106. doi:10.2174/1568006013337944. PMID 12769659. 
  • Masterman T, Hillert J (2004). "The telltale scan: APOE epsilon4 in multiple sclerosis.". Lancet neurology 3 (6): 331. doi:10.1016/S1474-4422(04)00763-X. PMID 15157846. 
  • Ashford JW (2004). "APOE genotype effects on Alzheimer's disease onset and epidemiology.". J. Mol. Neurosci. 23 (3): 157–65. doi:10.1385/JMN:23:3:157. PMID 15181244. 
  • Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004). "Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease.". J. Mol. Neurosci. 23 (3): 189–204. doi:10.1385/JMN:23:3:189. PMID 15181247. 
  • Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA (2004). "The role of viruses and of APOE in dementia.". Ann. N. Y. Acad. Sci. 1019: 15–8. doi:10.1196/annals.1297.003. PMID 15246985. 
  • Kolovou GD, Anagnostopoulou KK (2007). "Apolipoprotein E polymorphism, age and coronary heart disease.". Ageing Res. Rev. 6 (2): 94–108. doi:10.1016/j.arr.2006.11.001. PMID 17224309. 
  • Lambert JC, Amouyel P (2007). "Genetic heterogeneity of Alzheimer's disease: complexity and advances.". Psychoneuroendocrinology 32 Suppl 1: S62–70. doi:10.1016/j.psyneuen.2007.05.015. PMID 17659844. 
  • Raber J (2007). "Role of apolipoprotein E in anxiety.". Neural Plast. 2007: 91236. doi:10.1155/2007/91236. PMC 1940061. PMID 17710250. 
  • Ye J (2007). "Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus.". PLoS Pathog. 3 (8): e108. doi:10.1371/journal.ppat.0030108. PMC 1959368. PMID 17784784. 
  • Bennet AM, Di Angelantonio E, Ye Z, et al. (2007). "Association of apolipoprotein E genotypes with lipid levels and coronary risk.". JAMA 298 (11): 1300–11. doi:10.1001/jama.298.11.1300. PMID 17878422. 
  • Utermann G, Pruin N, Steinmetz A (1979). "Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man.". Clin. Genet. 15 (1): 63–72. doi:10.1111/j.1399-0004.1979.tb02028.x. PMID 759055. 
  • Moriyama K, Sasaki J, Matsunaga A, et al. (1992). "Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia.". Biochim. Biophys. Acta 1128 (1): 58–64. PMID 1356443. 
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External links

  1. REDIRECT Template:Lipoprotein metabolism