Apolipoprotein E

Apolipoprotein E (ApoE) is a class of is_associated_with::apolipoprotein found in the is_associated_with::chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. In peripheral tissues, ApoE is primarily produced by the is_associated_with::liver and is_associated_with::macrophages, and mediates is_associated_with::cholesterol metabolism in an is_associated_with::isoform-dependent manner. In the is_associated_with::central nervous system, ApoE is mainly produced by is_associated_with::astrocytes, and transports is_associated_with::cholesterol to is_associated_with::neurons via ApoE receptors, which are members of the is_associated_with::low density lipoprotein receptor gene family.

Function
APOE is 299 is_associated_with::amino acids long and transports is_associated_with::lipoproteins, fat-soluble is_associated_with::vitamins, and is_associated_with::cholesterol into the is_associated_with::lymph system and then into the blood. It is synthesized principally in the is_associated_with::liver, but has also been found in other tissues such as the is_associated_with::brain, is_associated_with::kidneys, and is_associated_with::spleen. In the nervous system, non-neuronal cell types, most notably astroglia and is_associated_with::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 is_associated_with::low density lipoprotein receptor gene family.

APOE was initially recognized for its importance in lipoprotein metabolism and is_associated_with::cardiovascular disease. Defects in APOE result in is_associated_with::familial dysbetalipoproteinemia aka type III is_associated_with::hyperlipoproteinemia (HLP III), in which increased plasma is_associated_with::cholesterol and triglycerides are the consequence of impaired clearance of is_associated_with::chylomicron, is_associated_with::VLDL and is_associated_with::LDL remnants. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including is_associated_with::Alzheimer's disease (AD), immunoregulation, and is_associated_with::cognition.

In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing is_associated_with::T cell proliferation, is_associated_with::macrophage functioning regulation, lipid antigen presentation facilitation (by is_associated_with::CD1) to natural killer T cell as well as modulation of is_associated_with::inflammation and is_associated_with::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.

Gene
The gene, ApoE, is mapped to chromosome 19 in a cluster with is_associated_with::Apolipoprotein C1 and the is_associated_with::Apolipoprotein C2. The APOE gene consists of four is_associated_with::exons and three is_associated_with::introns, totaling 3597 is_associated_with::base pairs. ApoE is transcriptionally activated by the is_associated_with::liver X receptor (an important regulator of is_associated_with::cholesterol, is_associated_with::fatty acid, and is_associated_with::glucose is_associated_with::homeostasis) and is_associated_with::peroxisome proliferator-activated receptor γ, is_associated_with::nuclear receptors that form is_associated_with::heterodimers with is_associated_with::Retinoid X receptors. In melanocytic cells APOE gene expression may be regulated by MITF.

Polymorphisms
ApoE is polymorphic,  with three major is_associated_with::alleles: ApoE2 (cys112, cys158), ApoE3 (cys112, arg158), and ApoE4 (arg112, arg158). Although these allelic forms differ from each other by only one or two is_associated_with::amino acids at positions 112 and 158, these differences alter apoE structure and function. These have physiological consequences:


 * E2 (rs7412) has an is_associated_with::allele frequency of approximately 7 percent. 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 is_associated_with::atherosclerosis. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and the is_associated_with::genetic disorder is_associated_with::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).  E2 has also been implicated in is_associated_with::Parkinson's disease. E2 is no longer associated with Parkinson disease in a larger population association study.
 * E3 (rs429358) has an allele frequency of approximately 79 percent. It is considered the "neutral" Apo E genotype.
 * E4 has an allele frequency of approximately 14 percent. E4 has been implicated in is_associated_with::atherosclerosis, is_associated_with::Alzheimer's disease, impaired is_associated_with::cognitive function, reduced is_associated_with::hippocampal volume, is_associated_with::HIV, faster disease progression in is_associated_with::multiple sclerosis,  unfavorable outcome after is_associated_with::traumatic brain injury, ischemic is_associated_with::cerebrovascular disease, is_associated_with::sleep apnea,  accelerated is_associated_with::telomere shortening and reduced is_associated_with::neurite outgrowth. A notable advantage of the E4 allele (relative to E2 and E3) is a positive association with higher levels of is_associated_with::vitamin D, which may help explain its prevalence despite its seeming complicity in various diseases or disorders.

However, there is much to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimers Disease. In addition, there is 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 is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease.

Alzheimer's disease
The E4 variant is the largest known genetic risk factor for late-onset sporadic is_associated_with::Alzheimer's 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 is_associated_with::amyloid. Alzheimer's disease is characterized by build-ups of aggregates of the is_associated_with::peptide is_associated_with::beta-amyloid. Apolipoprotein E enhances is_associated_with::proteolytic break-down of this peptide, both within and between cells. The is_associated_with::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.

The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at is_associated_with::Duke University Linkage studies were followed by association analysis confirming the role of the ApoE4 allele as a strong genetic risk factor for AD.

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 a 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. There is also evidence that the ApoE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4. Using genotype ApoE 3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype ApoE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the ApoE 3,4 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.

Atherosclerosis
Knockout mice that lack the apolipoprotein-E gene (ApoE−/−) develop extreme is_associated_with::hypercholesterolemia when fed a high-fat diet.