apolipoprotein e apolipoprotein e apolipoprotein e (apo-e) is a protein involved in the metabolism of fats in the body of mammals. a subtype is implicated in the alzheimer's disease and cardiovascular diseases. it is encoded in humans by the gene apoe. apoeavailable structurespdbortholog search: pdbe rcsb list of pdb id codes1b68, 1bz4, 1ea8, 1gs9, 1h7i, 1le2, 1le4, 1lpe, 1nfn, 1nfo, 1oef, 1oeg, 1or2, 1or3, 2kc3, 2kny, 2l7bidentifiersaliasesapoe, ad2, apo-e, ldlcq5, lpg, apolipoprotein e, apoe4external idsomim: 107741 mgi: 88057 homologene: 30951 genecards: apoe gene location (human)chr.chromosome 19 (human)band19q13.32start44,905,791 bpend44,909,393 bpgene location (mouse)chr.chromosome 7 (mouse)band7 a3|7 9.94 cmstart19,430,034 bpend19,433,113 bprna expression patternbgeehumanmouse (ortholog)top expressed inleft adrenal glandright lobe of livernucleus accumbensamygdalahypothalamuscaudate nucleusputamenspinal gangliaexternal globus palliduskidneytop expressed inentorhinal cortexleft lobe of liveryolk sacgallbladdersuperior frontal gyruslipmedian eminencearcuate nucleusoptic nerveglobus pallidusmore reference expression databiogpsmore reference expression datagene ontologymolecular function heparin binding very-low-density lipoprotein particle receptor binding low-density lipoprotein particle receptor binding lipoprotein particle binding phosphatidylcholine-sterol o-acyltransferase activator activity phospholipid binding cholesterol transfer activity protein homodimerization activity amyloid-beta binding protein binding tau protein binding metal chelating activity lipid transporter activity cholesterol binding antioxidant activity identical protein binding lipid binding cellular component cytoplasm membrane chylomicron extracellular region nucleus extracellular vesicle endocytic vesicle lumen very-low-density lipoprotein particle extracellular fluid endoplasmic reticulum extracellular exosome golgi apparatus blood microparticle extracellular matrix plasma membrane neuronal cell body early endosome low-density lipoprotein particle dendrite high-density lipoprotein particle intermediate-density lipoprotein particle biological process negative regulation of neuron apoptotic process response to dietary excess negative regulation of lipid transport across blood-brain barrier lipid transport positive regulation of lipid biosynthetic process regulation of axon extension positive regulation of postsynaptic membrane organization positive regulation of cholesterol esterification phospholipid efflux cholesterol catabolic process positive regulation of dendritic spine development receptor-mediated endocytosis retinoid metabolic process positive regulation of amyloid-beta formation lipid homeostasis lipoprotein biosynthetic process cholesterol homeostasis negative regulation of inflammatory response triglyceride metabolic process negative regulation of canonical wnt signaling pathway negative regulation of dendritic spine maintenance negative regulation of blood vessel endothelial cell migration nmda glutamate receptor clustering response to reactive oxygen species negative regulation of blood coagulation response to oxidative stress positive regulation of nitric-oxide synthase activity negative regulation of phospholipid efflux positive regulation of cholesterol efflux negative regulation of map kinase activity artery morphogenesis very-low-density lipoprotein particle remodeling regulation of neuronal synaptic plasticity negative regulation of dendritic spine development negative regulation of cholesterol biosynthetic process positive regulation of dendritic spine maintenance positive regulation of phospholipid efflux negative regulation of presynaptic membrane organization negative regulation of neuron death high-density lipoprotein particle clearance long-chain fatty acid transport lipoprotein metabolic process regulation of tau-protein kinase activity g protein-coupled receptor signaling pathway chylomicron remnant clearance cellular calcium ion homeostasis cholesterol metabolic process very-low-density lipoprotein particle clearance virion assembly negative regulation of lipid biosynthetic process cgmp-mediated signaling triglyceride catabolic process positive regulation of presynaptic membrane organization positive regulation of neurofibrillary tangle assembly ampa glutamate receptor clustering positive regulation of low-density lipoprotein particle receptor catabolic process positive regulation of lipid transport across blood-brain barrier fatty acid homeostasis nitric oxide mediated signal transduction transport cholesterol efflux regulation of gene expression negative regulation of cholesterol efflux regulation of amyloid-beta clearance neuron projection regeneration negative regulation of postsynaptic membrane organization steroid metabolic process regulation of cdc42 protein signal transduction lipid metabolism negative regulation of amyloid-beta formation positive regulation of membrane protein ectodomain proteolysis vasodilation intracellular transport synaptic transmission, cholinergic positive regulation of neuron death high-density lipoprotein particle assembly protein import high-density lipoprotein particle remodeling negative regulation of endothelial cell proliferation maintenance of location in cell negative regulation of platelet activation low-density lipoprotein particle remodeling positive regulation by host of viral process cytoskeleton organization regulation of neuron death reverse cholesterol transport lipoprotein catabolic process triglyceride homeostasis cellular oxidant detoxification lipid transport involved in lipid storage sources:amigo / quickgoorthologsspecieshumanmouseentrez34811816ensemblensg00000130203ensmusg00000002985uniprotp02649p08226refseq (mrna)nm_001302691nm_000041nm_001302688nm_001302689nm_001302690nm_009696nm_001305819nm_001305843nm_001305844refseq (protein)np_000032np_001289617np_001289618np_001289619np_001289620np_001292748np_001292772np_001292773np_033826location (ucsc)chr 19: 44.91 – 44.91 mbchr 7: 19.43 – 19.43 mbpubmed searchwikidataview/edit humanview/edit mouse apo-e belongs to a family of fat-binding proteins called apolipoproteins. in the circulation, it is present as part of several classes of lipoprotein particles, including chylomicron remnants, vldl, idl, and some hdl. apoe interacts significantly with the low-density lipoprotein receptor (ldlr), which is essential for the normal processing (catabolism) of triglyceride-rich lipoproteins. in peripheral tissues, apoe is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. in the central nervous system, apo-e is mainly produced by astrocytes and transports cholesterol to neurons via apoe receptors, which are members of the low density lipoprotein receptor gene family. apo-e is the principal cholesterol carrier in the brain. apo-e is required for cholesterol transportation from astrocytes to neurons. apoe qualifies as a checkpoint inhibitor of the classical complement pathway by complex formation with activated c1q. evolution apolipoproteins are not unique to mammals. many terrestrial and marine vertebrates have versions of them. it is believed that apoe arose via gene duplications of apoc1 before the fish-tetrapod split c. 400 million years ago. 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. 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 which had no effect on protein function (v174l, a18t, a135v). the fourth substitution (t61r) 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 exactly the same substitutions were found in denisovan apoe. about 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (cys112arg) 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. structure gene the gene, apoe, is mapped to chromosome 19 in a cluster with apolipoprotein c1 (apoc1) and the apolipoprotein c2 (apoc2). 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. in melanocytic cells apoe gene expression may be regulated by mitf. 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. polymorphisms snp: apolipoprotein egeneapoechromosome19external databasesensemblhuman snpviewdbsnp429358hapmap429358snpedia429358 apoe is polymorphic, with three major alleles (epsilon 2, epsilon 3, and epsilon 4): apoe-ε2 (cys112, cys158), apoe-ε3 (cys112, arg158), and apoe-ε4 (arg112, arg158). although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158, these differences alter apoe structure and function. there are several low-frequency polymorphisms of apoe. apoe5 comes in two subtypes e5f and e5s, based on migration rates. apoe5 e5f and apoe7 combined were found in 2.8% of japanese males. apoe7 is a mutation of apoe3 with two lysine residues replacing glutamic acid residues at positions 244 and 245. polymorphism worldwide allele frequency disease relevance ε2 (rs7412-t, rs429358-t) 8.4% this variant of the apoprotein binds poorly to cell surface receptors while e3 and e4 bind well. e2 is associated 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 the genetic disorder type iii hyperlipoproteinemia—94.4% of sufferers of such disease are e2/e2 but only ~2% of e2/e2 develop it, so other environmental and genetic factors are likely to be involved (such as cholesterol in the diet and age). e2 has also been implicated in parkinson's disease, but this finding was not replicated in a larger population association study. ε3 (rs7412-c, rs429358-t) 77.9% this variant is considered the "neutral" apoe genotype. ε4 (rs7412-c, rs429358-c) 13.7% e4 has been implicated in atherosclerosis, alzheimer's disease, impaired cognitive function, reduced hippocampal volume, hiv, faster disease progression in multiple sclerosis, unfavorable outcome after traumatic brain injury, ischemic cerebrovascular disease, sleep apnea, both the extension and shortening of telomeres, reduced neurite outgrowth, and covid-19. however, e4 has also been associated with enhanced vitamin d and calcium status, higher fecundity, protection against early childhood infection and malnutrition, and decreased fetal, perinatal, and infant mortality. much remains to be learned about the apoe isoforms, including the interaction of other protective genes. indeed, the apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms in some cases, so caution is advised before making determinant statements about the influence of apoe polymorphisms on cognition, development of alzheimer's disease, cardiovascular disease, telomere shortening, etc. many of the studies cited that purport these adverse outcomes are from single studies that have not been replicated and the research is based on unchecked assumptions about this isoform. as of 2007, there was 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 that the apoe4 isoform places individuals at increased risk for any infectious disease. however, the association between the apoe4 allele and alzheimer's disease has been shown to be weaker in minority groups differently compared to their caucasian counterparts. hispanics/latinos and african americans who were homozygous for the apoe4 allele had 2.2 and 5.7 times the odds, respectively of developing alzheimer's disease. caucasians who were homozygous for the allele had 12.5 times the odds. 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. 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 ldlr family. 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. 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. 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. 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) to natural killer t cell as well as modulation of inflammation and oxidation. 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. clinical significance alzheimer's disease as of 2012, the e4 variant was the largest known genetic risk factor for late-onset sporadic alzheimer's disease (ad) in a variety of ethnic groups. however, the e4 variant does not correlate with risk in every population. nigerian people have the highest observed frequency of the apoe4 allele in world populations, but ad is rare among them. this may be due to their low cholesterol levels. caucasian and japanese carriers of two 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. alzheimer's disease is characterized