Apolipoprotein E
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'''Apolipoprotein E''' (APOE) is an [[apoprotein]] found in the [[chylomicron]] that binds to a specific [[Receptor (biochemistry)|receptor]] on [[hepatocyte|liver cell]]s and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.<ref name="entrez">{{cite web | title = Entrez Gene: APOE apolipoprotein E| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348| accessdate = }}</ref>
==Function==
APOE<ref>{{cite journal |author=Singh PP, Singh M, Mastana SS |title=Genetic variation of apolipoproteins in North Indians |journal=Hum. Biol. |volume=74 |issue=5 |pages=673–82 |year=2002 |pmid=12495081 |doi=}}</ref> 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 acid]]s long and transports [[lipoprotein]]s, 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]], [[kidney]]s, and [[spleen]]. In the nervous system, non-neuronal cell types, most notably [[Astrocyte|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 (human)|chromosome 19]] in a cluster with [[Apolipoprotein C1]] and [[Apolipoprotein C2]]. ''ApoE'' consists of four [[exons]] and three [[introns]], totaling 3597 [[base pair]]s.
The gene is [[Polymorphism (biology)|polymorphic]]<ref>{{cite journal |author=Singh PP, Singh M, Mastana SS |title=APOE distribution in world populations with new data from India and the UK.|journal=Ann.Hum. Biol. |volume=33 |issue=3 |pages=279-308 |year=2006 |pmid=17092867 |doi=}}</ref> with three major [[allele]]s, ''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]].
{| class="wikitable"
|-
|-
| colspan="5" align="center" style="color: black; background: #ccccff" | '''Estimated human genotype frequency of ApoE'''<ref>{{cite journal |
journal = Exp Eye Res |
year = 2007 | month = May | volume = 84 | issue = 5 | pages = 801–811 |
title = Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease |
author = Hill JM, Bhattacharjee PS, Neumann DM |
pmid = 17007837}}</ref>
|-
! align="center" style="color: black; background: #ccccff" |Allele
! align="center" style="color: black; background: #ccccff" |ε2
! align="center" style="color: black; background: #ccccff" |ε3
! align="center" style="color: black; background: #ccccff" |ε4
|-
| align="center" style="color: black; background: #ccccff" | ε2
| align="center" |∼1–2%
| align="center" |∼15%
| align="center" |∼1–2%
|-
| align="center" style="color: black; background: #ccccff" | ε3
|
| align="center" |∼55%
| align="center" |∼25%
|-
| align="center" style="color: black; background: #ccccff" | ε4
|
|
| align="center" |∼1–2%
|}
==Alzheimer's Disease==
[[Alzheimer's Disease]] is characterized by [[amyloid plaque|plaques]] consisting of the [[peptide]] [[beta-amyloid]]. Apolipoprotein E enhances [[proteolytic]] break-down of this peptide, both within and between cells. Some [[isoform]]s 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.<ref name="Neuron">{{cite journal | author = 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 | date = [[2008-06-12]] | title = ApoE promotes the proteolytic degradation of Abeta | journal = Neuron | volume = 58 | issue = 5 | pages = 681-93 | publisher = Cell Press | location = United States | issn = 1097-4199 | pmid = 18549781 | doi = 10.1016/j.neuron.2008.04.010 | url = http://download.neuron.org/pdfs/0896-6273/PIIS0896627308003280.pdf | accessdate = 2008-06-16 | laysummary = http://www.sciencedaily.com/releases/2008/06/080611135123.htm | laysource = ScienceDaily | laydate = 2008-06-13 }}</ref>
Lipidated ApoE is more effective in breaking down beta-amyloid than unlipidated ApoE. Activating [[liver X receptor]]s creates more lipidated ApoE, which increases plaque removal.<ref name="Neuron"/>
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.<!--
--><ref name="pmid8346443">{{cite journal |author=Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA |title=Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families |journal=Science |volume=261 |issue=5123 |pages=921–3 |year=1993 |pmid=8346443 |doi=}}</ref><!--
-->
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.<!--
--><ref name="pmid17553421">{{cite journal |author=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 |title=GAB2 Alleles Modify Alzheimer's Risk in APOE varepsilon4 Carriers |journal= |volume=54 |issue=5 |pages=713–720 |year=2007 |pmid=17553421 |doi=10.1016/j.neuron.2007.05.022}} [http://www.neuron.org/content/article/fulltext?uid=PIIS0896627307003790&highlight=GAB2 Free full text] [http://download.neuron.org/pdfs/0896-6273/PIIS0896627307003790.pdf Free PDF] [http://www.tgen.org/research/index.cfm?pageid=1065 Genetic data in the public domain]</ref>
There is also evidence that the ApoE2 allele may serve a protective role in AD.<!--
--><ref name="pmid7920638">{{cite journal |author=Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE |title=Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease |journal=Nat. Genet. |volume=7 |issue=2 |pages=180–4 |year=1994 |pmid=7920638 |doi=10.1038/ng0694-180}}</ref>
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==
{{Reflist|2}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Mahley RW |title=Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. |journal=Science |volume=240 |issue= 4852 |pages= 622–30 |year= 1988 |pmid= 3283935 |doi= }}
*{{cite journal | author=Strittmatter WJ, Roses AD |title=Apolipoprotein E and Alzheimer disease. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 11 |pages= 4725–7 |year= 1995 |pmid= 7761390 |doi= }}
*{{cite journal | author=de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM |title=Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels. |journal=Hum. Mutat. |volume=4 |issue= 3 |pages= 178–94 |year= 1995 |pmid= 7833947 |doi= 10.1002/humu.1380040303 }}
*{{cite journal | author=Roses AD, Einstein G, Gilbert J, ''et al.'' |title=Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism. |journal=Ann. N. Y. Acad. Sci. |volume=777 |issue= |pages= 146–57 |year= 1996 |pmid= 8624078 |doi= }}
*{{cite journal | author=Beffert U, Danik M, Krzywkowski P, ''et al.'' |title=The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease. |journal=Brain Res. Brain Res. Rev. |volume=27 |issue= 2 |pages= 119–42 |year= 1998 |pmid= 9622609 |doi= }}
*{{cite journal | author=Mahley RW, Ji ZS |title=Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. |journal=J. Lipid Res. |volume=40 |issue= 1 |pages= 1–16 |year= 1999 |pmid= 9869645 |doi= }}
*{{cite journal | author=Mahley RW, Rall SC |title=Apolipoprotein E: far more than a lipid transport protein. |journal=Annual review of genomics and human genetics |volume=1 |issue= |pages= 507–37 |year= 2002 |pmid= 11701639 |doi= 10.1146/annurev.genom.1.1.507 }}
*{{cite journal | author=Parasuraman R, Greenwood PM, Sunderland T |title=The apolipoprotein E gene, attention, and brain function. |journal=Neuropsychology |volume=16 |issue= 2 |pages= 254–74 |year= 2002 |pmid= 11949718 |doi= }}
*{{cite journal | author=Bocksch L, Stephens T, Lucas A, Singh B |title=Apolipoprotein E: possible therapeutic target for atherosclerosis. |journal=Current drug targets. Cardiovascular & haematological disorders |volume=1 |issue= 2 |pages= 93–106 |year= 2003 |pmid= 12769659 |doi= }}
*{{cite journal | author=Masterman T, Hillert J |title=The telltale scan: APOE epsilon4 in multiple sclerosis. |journal=Lancet neurology |volume=3 |issue= 6 |pages= 331 |year= 2004 |pmid= 15157846 |doi= 10.1016/S1474-4422(04)00763-X }}
*{{cite journal | author=Ashford JW |title=APOE genotype effects on Alzheimer's disease onset and epidemiology. |journal=J. Mol. Neurosci. |volume=23 |issue= 3 |pages= 157–65 |year= 2004 |pmid= 15181244 |doi= }}
*{{cite journal | author=Huang Y, Weisgraber KH, Mucke L, Mahley RW |title=Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease. |journal=J. Mol. Neurosci. |volume=23 |issue= 3 |pages= 189–204 |year= 2004 |pmid= 15181247 |doi= }}
*{{cite journal | author=Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA |title=The role of viruses and of APOE in dementia. |journal=Ann. N. Y. Acad. Sci. |volume=1019 |issue= |pages= 15–8 |year= 2004 |pmid= 15246985 |doi= 10.1196/annals.1297.003 }}
*{{cite journal | author=Kolovou GD, Anagnostopoulou KK |title=Apolipoprotein E polymorphism, age and coronary heart disease. |journal=Ageing Res. Rev. |volume=6 |issue= 2 |pages= 94–108 |year= 2007 |pmid= 17224309 |doi= 10.1016/j.arr.2006.11.001 }}
*{{cite journal | author=Lambert JC, Amouyel P |title=Genetic heterogeneity of Alzheimer's disease: complexity and advances. |journal=Psychoneuroendocrinology |volume=32 Suppl 1 |issue= |pages= S62–70 |year= 2007 |pmid= 17659844 |doi= 10.1016/j.psyneuen.2007.05.015 }}
*{{cite journal | author=Raber J |title=Role of apolipoprotein E in anxiety. |journal=Neural Plast. |volume= |issue= |pages= 91236 |year= 2007 |pmid= 17710250 |doi= 10.1155/2007/91236 }}
*{{cite journal | author=Ye J |title=Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus. |journal=PLoS Pathog. |volume=3 |issue= 8 |pages= e108 |year= 2007 |pmid= 17784784 |doi= 10.1371/journal.ppat.0030108 }}
*{{cite journal | author=Bennet AM, Di Angelantonio E, Ye Z, ''et al.'' |title=Association of apolipoprotein E genotypes with lipid levels and coronary risk. |journal=JAMA |volume=298 |issue= 11 |pages= 1300–11 |year= 2007 |pmid= 17878422 |doi= 10.1001/jama.298.11.1300 }}
*{{cite journal | author=Utermann G, Pruin N, Steinmetz A |title=Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man. |journal=Clin. Genet. |volume=15 |issue= 1 |pages= 63–72 |year= 1979 |pmid= 759055 |doi= }}
*{{cite journal | author=Moriyama K, Sasaki J, Matsunaga A, ''et al.'' |title=Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia. |journal=Biochim. Biophys. Acta |volume=1128 |issue= 1 |pages= 58–64 |year= 1992 |pmid= 1356443 |doi= }}
}}
{{refend}}
==External links==
* {{MeshName|Apolipoproteins+E}}
{{Lipoproteins}}
[[Category:Apolipoproteins]]
[[Category:Alzheimer's disease]]
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