APOE4

Synonyms

APOE, Apolipoprotein E, Alzheimer Disease 2 (APOE*E4-Associated, Late Onset), Apolipoprotein E3, LDLCQ5, ApoE4, Apo-E, LPG, AD2, Apolipoproteins E

Description

APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids. APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance. Apoliproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma. As such, APOE associates with chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but shows a preferential binding to high-density lipoproteins (HDL). It also binds a wide range of cellular receptors including the LDL receptor/LDLR, the LDL receptor-related proteins LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR that mediate the cellular uptake of the APOE-containing lipoprotein particles. Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells. A main function of APOE is to mediate lipoprotein clearance through the uptake of chylomicrons, VLDLs, and HDLs by hepatocytes. APOE is also involved in the biosynthesis by the liver of VLDLs as well as their uptake by peripheral tissues ensuring the delivery of triglycerides and energy storage in muscle, heart and adipose tissues. By participating in the lipoprotein-mediated distribution of lipids among tissues, APOE plays a critical role in plasma and tissues lipid homeostasis. APOE is also involved in two steps of reverse cholesterol transport, the HDLs-mediated transport of cholesterol from peripheral tissues to the liver, and thereby plays an important role in cholesterol homeostasis. First, it is functionally associated with ABCA1 in the biogenesis of HDLs in tissues. Second, it is enriched in circulating HDLs and mediates their uptake by hepatocytes. APOE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting. APOE in also involved in innate and adaptive immune responses, controlling for instance the survival of myeloid-derived suppressor cells. APOE, may also play a role in transcription regulation through a receptor-dependent and cholesterol-independent mechanism, that activates MAP3K12 and a non-canonical MAPK signal transduction pathway that results in enhanced AP-1-mediated transcription of APP.Through its interaction with HCV envelope glycoprotein E2, participates in the attachment of HCV to HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface and to the assembly, maturation and infectivity of HCV viral particles. This interaction is probably promoted via the up-regulation of cellular autophagy by the virus.

KO Status

RenMab: F0

Drug Information

Drugs in clinical trials: 2
Latest Research Phase: Phase 2 Clinical

Drug Name

Code

Phase

Company

Indications

Clinical Trials

CN-105

CN-105

Phase 2 Clinical

Cerenova

Cerebral Hemorrhage

AEM-28

AEM-28

Phase 2 Clinical

Lipimetix

Hypercholesterolemia, Hyperlipoproteinemia Type II

COG-1410

COG-1410

Preclinical

Duke University

Brain Injuries, Traumatic, Alzheimer Disease, Subarachnoid Hemorrhage

COG-112

COG-112

Preclinical

Duke University

Multiple Sclerosis, Leukemia, Lymphocytic, Chronic, B-Cell

TML-6

TML-6

Preclinical

Merry Life Biomedical Co Ltd

Alzheimer Disease

References


Title

Authors

Source

Apolipoprotein E R112; R251G: a carboxy-terminal variant found in patients with hyperlipidemia and coronary heart disease

Kang A.K., Jenkins D.J.A., Wolever T.M.S., Huff M.W., Maguire G.F., Connelly P.W., Hegele R.A.,

Mutat. Res. 382:57-65(1997)

A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy

Matsunaga A., Sasaki J., Komatsu T., Kanatsu K., Tsuji E., Moriyama K., Koga T., Arakawa K., Oikawa S., Saito T., Kita T., Doi T.,

Kidney Int. 56:421-427(1999)

Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice

Ishigaki Y., Oikawa S., Suzuki T., Usui S., Magoori K., Kim D.H., Suzuki H., Sasaki J., Sasano H., Okazaki M., Toyota T., Saito T., Yamamoto T.T.,

J. Biol. Chem. 275:31269-31273(2000)

Familial splenomegaly: macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (delta149 Leu)]

Nguyen T.T., Kruckeberg K.E., O'Brien J.F., Ji Z.-S., Karnes P.S., Crotty T.B., Hay I.D., Mahley R.W., O'Brien T.,

J. Clin. Endocrinol. Metab. 85:4354-4358(2000)

Apolipoprotein E3Basel: new insights into a highly conserved protein region

Miserez A.R., Scharnagl H., Muller P.Y., Mirsaidi R., Stahelin H.B., Monsch A., Marz W., Hoffmann M.M.,

Eur. J. Clin. Invest. 33:677-685(2003)

Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 non-genetic cardiovascular disease risk factors

Morabia A., Cayanis E., Costanza M.C., Ross B.M., Flaherty M.S., Alvin G.B., Das K., Gilliam T.C.,

Hum. Mol. Genet. 12:2733-2743(2003)

Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation

Faivre L., Saugier-Veber P., Pais de Barros J.-P., Verges B., Couret B., Lorcerie B., Thauvin C., Charbonnier F., Huet F., Gambert P., Frebourg T., Duvillard L.,

Eur. J. Hum. Genet. 13:1186-1191(2005)

APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy

Rovin B.H., Roncone D., McKinley A., Nadasdy T., Korbet S.M., Schwartz M.M.,

N. Engl. J. Med. 357:2522-2524(2007)

Quantitative detection of single amino acid polymorphisms by targeted proteomics

Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H., Lin X., Zeng R., Wu J.R.,

J. Mol. Cell Biol. 3:309-315(2011)

Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia

Solanas-Barca M., de Castro-Oros I., Mateo-Gallego R., Cofan M., Plana N., Puzo J., Burillo E., Martin-Fuentes P., Ros E., Masana L., Pocovi M., Civeira F., Cenarro A.,

Atherosclerosis 222:449-455(2012)