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Apolipoprotein E (APOE) is an apoprotein found in the chylomicron 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]
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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. 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 APOE gene, ApoE, is mapped to chromosome 19 in a cluster with Apolipoprotein C1 and Apolipoprotein C2. ApoE consists of four exons and three introns, totaling 3597 base pairs.
The gene is polymorphic[3] with three major alleles, ApoE2, ApoE3, ApoE4, which translate into three isoforms of the protein: normal - ApoE-ε3; dysfunctional - ApoE-ε2 and ApoE-ε4. These isoforms differ from each other only by single amino acid substitutions at positions 112 and 158, but have profound physiological consequences.
- E2 is associated with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis.
- E4 has been implicated in atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth.
ApoE is a target gene of liver X receptor, a nuclear receptor member that play role in metabolism regulation of cholesterol, fatty acid, and glucose homeostasis.
| Estimated human genotype frequency of ApoE[4] | ||||
| Allele | ε2 | ε3 | ε4 | |
|---|---|---|---|---|
| ε2 | ∼1–2% | ∼15% | ∼1–2% | |
| ε3 | ∼55% | ∼25% | ||
| ε4 | ∼1–2% | |||
Alzheimer's Disease
Alzheimer's Disease is characterized by plaques consisting 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.[5]
Lipidated ApoE is more effective in breaking down beta-amyloid than unlipidated ApoE. Activating liver X receptors creates more lipidated ApoE, which increases plaque removal.[5]
The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University. Linkage studies were followed by association analysis confirming the role of the ApoE4 allele.[6]
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. Among ApoE4 carriers, another gene, GAB2, is thought to further influence the risk of getting AD.[7]
There is also evidence that the ApoE2 allele may serve a protective role in AD.[8]
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.
References
- ^ "Entrez Gene: APOE apolipoprotein E".
- ^ Singh PP, Singh M, Mastana SS (2002). "Genetic variation of apolipoproteins in North Indians". Hum. Biol. 74 (5): 673–82. PMID 12495081.
- ^ 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. PMID 17092867.
- ^ Hill JM, Bhattacharjee PS, Neumann DM (May 2007). "Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease". Exp Eye Res 84 (5): 801–811. PMID 17007837.
- ^ a b 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 58 (5): 681-93. United States: Cell Press. doi:. ISSN 1097-4199. PMID 18549781. Retrieved on 2008-06-16. Lay summary – ScienceDaily (2008-06-13).
- ^ 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. PMID 8346443.
- ^ Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA (2007). "GAB2 Alleles Modify Alzheimer's Risk in APOE varepsilon4 Carriers" 54 (5): 713–720. doi:. PMID 17553421. Free full text Free PDF Genetic data in the public domain
- ^ 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:. PMID 7920638.
Further reading
- Mahley RW (1988). "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.". Science 240 (4852): 622–30. PMID 3283935.
- Strittmatter WJ, Roses AD (1995). "Apolipoprotein E and Alzheimer disease.". Proc. Natl. Acad. Sci. U.S.A. 92 (11): 4725–7. 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:. 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. 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. 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:. PMID 11701639.
- Parasuraman R, Greenwood PM, Sunderland T (2002). "The apolipoprotein E gene, attention, and brain function.". Neuropsychology 16 (2): 254–74. 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. PMID 12769659.
- Masterman T, Hillert J (2004). "The telltale scan: APOE epsilon4 in multiple sclerosis.". Lancet neurology 3 (6): 331. doi:. PMID 15157846.
- Ashford JW (2004). "APOE genotype effects on Alzheimer's disease onset and epidemiology.". J. Mol. Neurosci. 23 (3): 157–65. 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. 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:. PMID 15246985.
- Kolovou GD, Anagnostopoulou KK (2007). "Apolipoprotein E polymorphism, age and coronary heart disease.". Ageing Res. Rev. 6 (2): 94–108. doi:. PMID 17224309.
- Lambert JC, Amouyel P (2007). "Genetic heterogeneity of Alzheimer's disease: complexity and advances.". Psychoneuroendocrinology 32 Suppl 1: S62–70. doi:. PMID 17659844.
- Raber J (2007). "Role of apolipoprotein E in anxiety.". Neural Plast.: 91236. doi:. 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:. 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:. 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. 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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