- Apolipoprotein E
Apolipoprotein E (APOE) is an
apoprotein found in thechylomicron that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.cite web | title = Entrez Gene: APOE apolipoprotein E| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348| accessdate = ]Function
APOE [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=] is essential for the normal
catabolism oftriglyceride -richlipoprotein constituents. APOE was initially recognized for its importance in lipoprotein metabolism andcardiovascular disease . More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, includingAlzheimer'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 forcerebral palsy , according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result infamilial dysbetalipoproteinemia , or type IIIhyperlipoproteinemia (HLP III), in which increased plasmacholesterol and triglycerides are the consequence of impaired clearance ofchylomicron ,VLDL andLDL remnants.APOE is 299
amino acid s long and transportslipoprotein s, fat-solublevitamins , andcholesterol into thelymph system and then into the blood. It is synthesized principally in theliver , but has also been found in other tissues such as thebrain ,kidney s, andspleen . In the nervous system, non-neuronal cell types, most notably astroglia andmicroglia , 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 conservedlow density lipoprotein receptor gene family .Gene
The APOE gene, "ApoE", is mapped to chromosome 19 in a cluster with
Apolipoprotein C1 andApolipoprotein C2 . "ApoE" consists of fourexons and threeintrons , totaling 3597base pair s.The gene is polymorphic [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=] with three major
allele s, "ApoE2", "ApoE3", "ApoE4", which translate into threeisoforms of the protein: normal - ApoE-ε3; dysfunctional - ApoE-ε2 and ApoE-ε4. These isoforms differ from each other only by singleamino 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 foratherosclerosis .* E4 has been implicated in
atherosclerosis andAlzheimer's disease , impairedcognitive function , and reducedneurite outgrowth."ApoE" is a target gene of
liver X receptor , anuclear receptor member that play role inmetabolism regulation ofcholesterol ,fatty acid , andglucose homeostasis .Alzheimer's Disease
Alzheimer's Disease is characterized by plaques consisting of thepeptide beta-amyloid . Apolipoprotein E enhancesproteolytic break-down of this peptide, both within and between cells. Someisoform 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.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 ]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.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. 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=]
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. 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] ]
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