Apolipoprotein E - Wikipedia
Apolipoprotein E (ApoE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.[1] In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism in an isoform-dependent manner. In the central nervous system, ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene 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 remnants[citation needed]. 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.
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) [3] to natural killer T cell as well as modulation of inflammation and oxidation.[4]
The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance[31] while working in the Roses lab at Duke University[32] Linkage studies were followed by association analysis confirming the role of the ApoE4 allele as a strong genetic risk factor for AD.[19][20]
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. Yet those with two e4 alleles have up to 20 times the risk of developing AD.[citation needed] There is also evidence that the ApoE2 allele may serve a protective role in AD.[33] Thus, the genotype most at risk for Alzheimer disease and at an 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 disease. The genotype ApoE 2,3 is considered at lower risk for Alzheimer 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.
The connection between neuron failure in Alzheimer disease and depleted myelin cholesterol (via ApoE deficiency) has also been described in Cholesterol Depletion and consequently is a known adverse drug reaction to statin therapy.[34][35][36][37][38]
Statin Pathway edit
^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
Apolipoprotein E (ApoE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.[1] In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism in an isoform-dependent manner. In the central nervous system, ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family.
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Function
APOE [2] 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.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 remnants[citation needed]. 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.
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) [3] to natural killer T cell as well as modulation of inflammation and oxidation.[4]
Gene
The protein, ApoE, is mapped to chromosome 19 in a cluster with Apolipoprotein C1 and the Apolipoprotein C2. 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 receptorγ, nuclear receptors that form heterodimers with Retinoid X receptors.[5] In melanocytic cells APOE gene expression may be regulated by MITF.[6]Polymorphisms
ApoE is polymorphic[7][8] with three major isoforms: ApoE2 (cys112, cys158), ApoE3 (cys112, arg158), and ApoE4 (arg112, arg158).[9] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,[10][11][12] these differences alter apoE structure and function. These have physiological consequences:- E2 (rs7412) is found in approximately 7 percent of the population.[13] This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.[14] 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 such patients are E2/E2, while only ∼2% of E2/E2 develop the disease, so other environmental and genetic factors are likely to be involved (such as cholesterol in the diet and age).[15][16][17] E2 has also been implicated in Parkinson's disease[18]
- E3 (rs429358) is found in approximately 79 percent of the population.[13] It is considered the "neutral" Apo E genotype.
- E4 is found in approximately 14 percent of the population.[13] E4 has been implicated in atherosclerosis, Alzheimer's disease,[19][20] impaired cognitive function,[21][22] reduced hippocampal volume,[22] faster disease progression in Multiple Sclerosis,[23] unfavorable outcome after traumatic brain injury,[24] ischemic cerebrovascular disease,[25] sleep apnea,[26][27] and reduced neurite outgrowth.[28]
Alzheimer disease
The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer disease (AD) in a variety of ethnic groups. Caucasian and Japanese carriers of 2 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. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid.[29] Alzheimer disease is characterized by build-ups of aggregates of the peptide beta-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 catalyzing these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.[30]The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance[31] while working in the Roses lab at Duke University[32] Linkage studies were followed by association analysis confirming the role of the ApoE4 allele as a strong genetic risk factor for AD.[19][20]
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. Yet those with two e4 alleles have up to 20 times the risk of developing AD.[citation needed] There is also evidence that the ApoE2 allele may serve a protective role in AD.[33] Thus, the genotype most at risk for Alzheimer disease and at an 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 disease. The genotype ApoE 2,3 is considered at lower risk for Alzheimer 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.
The connection between neuron failure in Alzheimer disease and depleted myelin cholesterol (via ApoE deficiency) has also been described in Cholesterol Depletion and consequently is a known adverse drug reaction to statin therapy.[34][35][36][37][38]
| Estimated worldwide human allele frequencies of ApoE *[39] | ||||
| Allele | ε2 | ε3 | ε4 | |
|---|---|---|---|---|
| General Frequency | 8.4% | 77.9% | 13.7% | |
| AD Frequency | 3.9% | 59.4% | 36.7% | |
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
