Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases.[5] It is encoded in humans by the geneAPOE.
Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them.[12] 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.[13]
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.[14]
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.[15][13]
APOE is 299 amino acids long and contains multiple amphipathicα-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.[18]
APOE is polymorphic,[19][20] with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158).[5][21][22] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,[23][24][25] 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.[26][unreliable medical source] APOE7 is a mutation of APOE3 with two lysine residues replacing glutamic acid residues at positions 244 and 245.[27]
This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.[28] 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 disordertype III hyperlipoproteinemia—94.4% of people with 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).[29][30][31] E2 has also been implicated in Parkinson's disease,[32] but this finding was not replicated in a larger population association study.[33]
Much remains to be learned about the APOE isoforms, including the interaction of other protective genes.[58] Indeed, the apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms in some cases,[58] 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.[59]
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.[9]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.[60][9] The APOE4 allele has an even stronger effect in East Asian populations, with Japanese populations have 33 times the odds compared to other populations.[61] Caucasians who were homozygous for the allele had 12.5 times the odds.[60][9]
Function
As a component of the lipoprotein lipid transport system, APOE facilitates the transport of lipids, fat-soluble vitamins, and cholesterol via the blood. It interacts with the LDL receptor to facilitate endocytosis of VLDL remnants. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen.[21] APOE synthesized in the liver associates with HDL which can then distribute it to newly formed VLDL or chylomicron particles to facilitate their eventual uptake by the liver.
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.[62] There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.[63]
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.[64][7] 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.[5] 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.[65]
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)[66] to natural killer T cell as well as modulation of inflammation and oxidation.[67] 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.[68]
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.[69] 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,[70] but AD is rare among them.[70][71] This may be due to their low cholesterol levels.[70][71][72][73] 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.[74] Alzheimer's disease is characterized by build-ups of aggregates of the peptidebeta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform APOE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.[75]
Recently, the amyloid hypothesis of Alzheimer's disease has been questioned, and an article in Science claimed that "Just as removing smoke does not extinguish a fire, reducing amyloid plaques may not affect the course of Alzheimer's disease."[76] The role that the E4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact that reelin signaling emerges to be one of the key processes involved in Alzheimer's disease[77] and the E4 variant is shown to interact with ApoER2, one of the neuronal reelin receptors, thereby obstructing reelin signaling.[77]
Although 40–65% of AD patients have at least one copy of the ε4 allele, APOE4 is not a determinant of the disease. At least one-third of patients with AD are APOE4 negative and some APOE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.[78] There is also evidence that the APOE2 allele may serve a protective role in AD.[79] Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype APOE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (APOE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (APOE2,2) also have an odds ratio of 0.6.[80]
Estimated worldwide human allele frequencies of APOE in Caucasian population[80]
Allele
ε2
ε3
ε4
General frequency
8.4%
77.9%
13.7%
AD frequency
3.9%
59.4%
36.7%
While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a 2002 study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.[73] Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.[73]
Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.[81]
APOE-ε4 increases the risk not only for AD but also for dementia in pure alpha-synucleinopathies.[82] The influence of APOE-ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespread neurodegeneration.[83]
APOE−/− knockout mice show marked attenuation of cerebral malaria and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the blood–brain barrier.[85] Human studies have shown that the APOE2 polymorphism correlates with earlier infection, and APOE3/4 polymorphisms increase likelihood of severe malaria.[86]
Lyme disease
Borrelia burgdorferi, the causative agent of Lyme disease, is a host-adapted pathogen that acquires environmental cholesterol to form glycolipids for use in cell membrane maintenance. In one experiment in 2015, mice engineered with apoE deficiency were infected with Borrelia spirochetes. The knockout mice suffered from an increased spirochete burden in joints, as well as inflamed ankles, when compared with wild-type mice. This study suggests that apoE deficiency (and potentially other hyperlipidemias) may be a risk factor in the pathogenicity of Lyme disease.
Interactions
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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Statin pathway edit
^The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
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Further reading
Ashford JW (2004). "APOE genotype effects on Alzheimer's disease onset and epidemiology". Journal of Molecular Neuroscience. 23 (3): 157–165. doi:10.1385/JMN:23:3:157. PMID 15181244. S2CID 14864342.
Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J (July 1998). "The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease". Brain Research. Brain Research Reviews. 27 (2): 119–142. doi:10.1016/S0165-0173(98)00008-3. PMID 9622609. S2CID 28731779.
Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, et al. (September 2007). "Association of apolipoprotein E genotypes with lipid levels and coronary risk". JAMA. 298 (11): 1300–1311. doi:10.1001/jama.298.11.1300. PMID 17878422.
Bocksch L, Stephens T, Lucas A, Singh B (December 2001). "Apolipoprotein E: possible therapeutic target for atherosclerosis". Current Drug Targets - Cardiovascular & Hematological Disorders. 1 (2): 93–106. doi:10.2174/1568006013337944. PMID 12769659.
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". Human Mutation. 4 (3): 178–194. doi:10.1002/humu.1380040303. PMID 7833947. S2CID 41959843.
Gunzburg MJ, Perugini MA, Howlett GJ (December 2007). "Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E". The Journal of Biological Chemistry. 282 (49): 35831–35841. doi:10.1074/jbc.M706425200. PMID 17916554.
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". Journal of Molecular Neuroscience. 23 (3): 189–204. doi:10.1385/JMN:23:3:189. PMID 15181247. S2CID 40135107.
Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA (June 2004). "The role of viruses and of APOE in dementia". Annals of the New York Academy of Sciences. 1019 (1): 15–18. Bibcode:2004NYASA1019...15I. doi:10.1196/annals.1297.003. PMID 15246985. S2CID 28979273.
Kolbe D, da Silva NA, Dose J, Torres GG, Caliebe A, Krause-Kyora B, Nebel A (May 2023). "Current allele distribution of the human longevity gene APOE in Europe can mainly be explained by ancient admixture". Aging Cell. 22 (5). Wiley: e13819. doi:10.1111/acel.13819. PMC 10186601. PMID 36951219.
Kolovou GD, Anagnostopoulou KK (August 2007). "Apolipoprotein E polymorphism, age and coronary heart disease". Ageing Research Reviews. 6 (2): 94–108. doi:10.1016/j.arr.2006.11.001. PMID 17224309. S2CID 35607578.
Lambert JC, Amouyel P (August 2007). "Genetic heterogeneity of Alzheimer's disease: complexity and advances". Psychoneuroendocrinology. 32 (Suppl 1): S62–S70. doi:10.1016/j.psyneuen.2007.05.015. PMID 17659844. S2CID 8114580.
Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (February 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology. 9 (2): 106–118. doi:10.1038/nrneurol.2012.263. PMC 3726719. PMID 23296339.
Mahley RW, Ji ZS (January 1999). "Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E". Journal of Lipid Research. 40 (1): 1–16. doi:10.1016/S0022-2275(20)33334-4. PMID 9869645.
Mahley RW, Rall SC (2002). "Apolipoprotein E: far more than a lipid transport protein". Annual Review of Genomics and Human Genetics. 1 (1): 507–537. doi:10.1146/annurev.genom.1.1.507. PMID 11701639.
Mahley RW (April 1988). "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology". Science. 240 (4852): 622–630. Bibcode:1988Sci...240..622M. doi:10.1126/science.3283935. PMID 3283935.
Masterman T, Hillert J (June 2004). "The telltale scan: APOE epsilon4 in multiple sclerosis". The Lancet. Neurology. 3 (6): 331. doi:10.1016/S1474-4422(04)00763-X. PMID 15157846. S2CID 54404547.
Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, et al. (September 1992). "Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia". Biochimica et Biophysica Acta. 1128 (1): 58–64. doi:10.1016/0005-2760(92)90257-V. PMID 1356443.
Parasuraman R, Greenwood PM, Sunderland T (April 2002). "The apolipoprotein E gene, attention, and brain function". Neuropsychology. 16 (2): 254–274. doi:10.1037/0894-4105.16.2.254. PMC 1350934. PMID 11949718.
Raber J (2007). "Role of apolipoprotein E in anxiety". Neural Plasticity. 2007: 91236. doi:10.1155/2007/91236. PMC 1940061. PMID 17710250.
Roses AD, Einstein G, Gilbert J, Goedert M, Han SH, Huang D, et al. (January 1996). "Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism". Annals of the New York Academy of Sciences. 777 (1): 146–157. Bibcode:1996NYASA.777..146R. doi:10.1111/j.1749-6632.1996.tb34413.x. PMID 8624078. S2CID 9145181.
Strittmatter WJ, Roses AD (May 1995). "Apolipoprotein E and Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America. 92 (11): 4725–4727. Bibcode:1995PNAS...92.4725S. doi:10.1073/pnas.92.11.4725. PMC 41779. PMID 7761390.
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Ye J (August 2007). "Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus". PLOS Pathogens. 3 (8): e108. doi:10.1371/journal.ppat.0030108. PMC 1959368. PMID 17784784.
1b68: APOLIPOPROTEIN E4 (APOE4), 22K FRAGMENT
1bz4: APOLIPOPROTEIN E3 (APO-E3), TRUNCATION MUTANT 165
1ea8: APOLIPOPROTEIN E3 22KD FRAGMENT LYS146GLU MUTANT
1gs9: APOLIPOPROTEIN E4, 22K DOMAIN
1h7i: APOLIPOPROTEIN E3 22KD FRAGMENT LYS146GLN MUTANT
1le2: STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E
1le4: STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E
1lpe: THREE-DIMENSIONAL STRUCTURE OF THE LDL RECEPTOR-BINDING DOMAIN OF HUMAN APOLIPOPROTEIN E
1nfn: APOLIPOPROTEIN E3 (APOE3)
1nfo: APOLIPOPROTEIN E2 (APOE2, D154A MUTATION)
1or2: APOLIPOPROTEIN E3 (APOE3) TRUNCATION MUTANT 165
1or3: APOLIPOPROTEIN E3 (APOE3), TRIGONAL TRUNCATION MUTANT 165
