Apolipoprotein E

Apolipoprotein E (APOE) is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.^[1]

Function

APOE^[2] is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. 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 amount 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.^[3]

Neonates with brain injuries and/or defects who also have abnormalities in the APOE gene may have an increased risk for cerebral palsy, according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL remnants.

APOE 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.

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. In melanocytic cells APOE gene expression may be regulated by MITF.^[4]

ApoE is polymorphic^[5][6] with three major isoforms, ApoE2, ApoE3, ApoE4, which translate into three alleles of the gene:

• Normal: ApoE-ε3
• Dysfunctional: ApoE-ε2 and ApoE-ε4

These allelic forms differ from each other only by amino acid substitutions at positions 112 and 158.^[7].On Entrez SNP these are positions 130 and 176, rs429358 and rs7412 respectively; Entrez SNP positioning and positioning within Ensembl Genome Browser as 130 and 176 being those of the preprotein, intracellular proteolysis shifting these to positions 112 and 158. The E2 allele has a Cys at positions 112 and 158 in the receptor-binding region of ApoE. The E3 allele is Cys-112 and Arg-158. The ApoE E4 allele is Arg at both positions.^[8] These have physiological consequences:

• E2 is associated with the genetic disorder hyperlipoproteinemia type III and 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 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.^[9][10][11]

• E3 is found in approximately 64 percent of the population. It is considered the "neutral" Apo E genotype.

• E4 has been implicated in atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth.

ApoE is a target gene of the liver X receptor, a nuclear receptor member that plays a role in the metabolism regulation of cholesterol, fatty acid, and glucose homeostasis.

Alzheimer's Disease

The E4 variant is the largest known genetic risk factor for late-onset sporadic 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 amyloid (insoluble protein aggregates). Alzheimer's 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. Some isoforms 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.^[12]

The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance^[13] while working in the Roses lab at Duke University^[14] Linkage studies were followed by association analysis confirming the role of the ApoE4 allele.^[15]

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. There is also evidence that the ApoE2 allele may serve a protective role in AD.^[16] Thus, the genotype most at risk for Alzheimer's disease and at 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's disease. The genotype ApoE 2,3 is considered at less risk for Alzheimer's 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's disease and depleted myelin cholesterol (via ApoE deficiency) has also been described in Cholesterol Depletion and consequently is a known statin therapy adverse drug reaction.^{[17][18][19][20][21]}

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^[22]

References

Further reading

External links

• MeSH Apolipoproteins+E