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FLASH GENE
Symbol APOE contributors: mct/pgu - updated : 03-12-2013
HGNC name apolipoprotein E
HGNC id 613
Corresponding disease
AD2 Alzheimer disease associated with APOE4
APOE familial dysbetalipoproteinemia, hyperlipoproteinemia type III
ARMDS2 age related macular dystrophy, 2
SBHD sea-blue histiocyte disease
Location 19q13.32      Physical location : 45.409.038 - 45.412.649
Synonym name
  • apoprotein
  • apolipoprotein E3
  • Alzheimer disease 2 (APOE*E4-associated, late onset)
  • Synonym symbol(s) MGC1571, Apo-E, LPG, LDLCQ5
    DNA
    TYPE functioning gene
    STRUCTURE 3.61 kb     4 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked Y status confirmed
    Physical map
    LOC147711 19q13.32 similar to zinc finger protein 285 ZNF180 19q13.1-q13.3 zinc finger protein 180 (HHZ168) UNQ9366 19q13.32 GPAD9366 LOC388550 19 similar to CEACAM5 protein LOC390941 19 LOC390941 LOC147710 19q13.32 hypothetical LOC147710 PVR 19q13.2 poliovirus receptor CEAL1 19q13.32 carcinoembryonic antigen-like 1 LOC388551 19 similar to carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) BCL3 19q13.2 B-cell CLL/lymphoma 3 CBLC 19q13.2-q13.3 Cas-Br-M (murine) ecotropic retroviral transforming sequence c LU 19q12-q13 Lutheran blood group (Auberger b antigen included) PVRL2 19q13.2-q13.4 poliovirus receptor-related 2 (herpesvirus entry mediator B) TOMM40 19q13 translocase of outer mitochondrial membrane 40 homolog (yeast) APOE 19q13.2 apolipoprotein E APOC1 19q13.2 apolipoprotein C-I APOC4 19q13.2 apolipoprotein C-IV APOC2 19q13.2 apolipoprotein C-II CLPTM1 19q13.2 cleft lip and palate associated transmembrane protein 1 RELB 19q13.32 v-rel reticuloendotheliosis viral oncogene homolog B, nuclear factor of kappa light polypeptide gene enhancer in B-cells 3 (avian) SFRS16 19q13.3 splicing factor, arginine/serine-rich 16 (suppressor-of-white-apricot homolog, Drosophila) ZNF342 19q13.32 zinc finger protein 342 GEMIN7 19q13.32 gem (nuclear organelle) associated protein 7 EIF5AP3 19q13.2 eukaryotic translation initiation factor 5A pseudogene 3 LOC284352 19q13.32 hypothetical protein LOC284352 FLJ33600 19q13.32 FLJ33600 protein MGC2650 19q13.32 hypothetical protein MGC2650 LOC388552 19 similar to BC043666 protein XTP7 19q13.32 protein 7 transactivated by hepatitis B virus X antigen (HBxAg) MARK4 19q13.2 MAP/microtubule affinity-regulating kinase 4 CKM 19q13.2 creatine kinase, muscle LOC390943 19 similar to 40S ribosomal protein S16 KLC2L 19q13.3 similar to 40S ribosomal protein S16 ERCC2 19q13.3 excision repair cross-complementing rodent repair deficiency, complementation group 2 (xeroderma pigmentosum D)
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - - - 34.15 299 - 2010 21114327
  • exhibits lower lipid binding ability than APOE4 as a consequence of a rearrangement involving the segment spanning AAs 261-272 in the C-terminal domain
  • APOE4 binds less strongly than APOE3 to HDL(3), consistent with apoE-lipid interactions being relatively unimportant for binding to HDL
  • stimulates neurite outgrowth
  • at residues 112 or 158, apoE3 has a cysteine at residue 112 and an arginine at residue 158
  • - - - 34.15 299 primarily produced by astrocytes in the brain, but neurons can also produce APOE4 under stress conditions 2010 21114327
  • exhibits better lipid binding ability than APOE3 as a consequence of a rearrangement involving the segment spanning AAs 261-272
  • stronger lipid binding ability of APOE4 relative to that of APOE3
  • differs from the other two common isoforms (apoE2, apoE3) at residues 112 or 158, having arginines at both positions
  • may perturb mitochondrial respiratory function in the brain, rendering subjects with apoE4 more susceptible to AD neuropathology
  • detrimental effects of apoE4 on mitochondria can be mitigated by genetic and pharmacologic interference with apoE4 domain interaction
  • increases APP oligomers in the brain, which may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD
  • inhibits neurite outgrowth
  • should be considered a major gene, with semidominant inheritance, for late-onset AD
  • 4 - 1223 34.2 317 - 2005 16091415
    with two alternative stop codons
    - - 5515 - - liver 2005 16091415
    also called APOEAS2
    - - - - 219 parotis, kidney, liver, lung, thymus, small intestine 2005 16091415
  • also called APOEAS1
  • antisense transcript
  • - - - - - - 2011 21118811
  • at residues 112 or 158 having cysteines
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
    Endocrineadrenal gland   highly
    Lymphoid/Immunespleen   moderately
    Nervousbrain   predominantly Homo sapiens
    Reproductivefemale systemovary  moderately
    Respiratorylung   moderately
    Urinarykidney   highly
    Visualeyeretina  moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningretinal pigment epithelium (RPE)  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousastrocyte Homo sapiens
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N-terminal domain of interaction with the LDL receptor and heparin sulfate proteoglycan
  • a hinge region from the C-terminal lipid binding domain
  • an heparin binding region
  • conjugated GlycoP
    HOMOLOGY
    interspecies homolog to rattus Apoe (71.34 pc)
    homolog to murine Apoe (73.70 pc)
    intraspecies homolog to APOA4
    Homologene
    FAMILY
  • APOA1/APOA4/APOE family
  • CATEGORY receptor membrane , transport carrier
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    basic FUNCTION
  • clearance of chylomicrons, remnants and beta-VLDL from the plasma
  • modulates glutamate receptor function and synaptic plasticity by regulating apoE receptor recycling in neurons, with APOE3 stimulating and APOE4 inhibiting this process
  • in the nervous system, functions as a major carrier and distributor of cholesterol and other lipids, which are essential components of neuronal membranes and myelin sheaths
  • is required for maintenance of the dentate gyrus neural progenitor pool
  • APOE-induced intracellular APP degradation is mediated by the cholesterol efflux function of APOE, which lowers cellular cholesterol levels and subsequently facilitates the intracellular trafficking of APP to lysosomes for degradation
  • plays an important role in lipoprotein metabolism
  • role of APOE and COMT genes in prospective and retrospective memory traits
  • putative functional role of APOE in modulating myelin-related processes in the brain
  • major cholesterol carrier that supports lipid transport and injury repair in the brain
  • influences soluble APP metabolism not through direct binding to soluble APP in solution but through its actions with other interacting receptors/transporters and cell surfaces
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism lipid/lipoprotein
    signaling sensory transduction/vision
    fatty acid and sterol
    a component
  • constituent of several lipoproteins including chylomicrons, remnants, VLDL, IDL, some HDLs
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to LDL receptor
  • binding with MYOC promoter SNP (increased intraocular pressure in primary open angle glaucoma
  • binding to heparin
  • APOE4 binds preferentially to very low-density lipoproteins (VLDLs), whereas APOE3 binds preferentially to high-density lipoproteins (HDLs), resulting in different plasma cholesterol levels for the two isoforms
  • APOE associated with APOB-carrying lipoproteins has an upregulatory role on ABCA1 expression, and induction of Sp1 phosphorylation is a mechanism by which APOE upregulates ABCA1 expression
  • mechanistic link between APOE-regulated cholesterol homeostasis and APP degradation
  • APP endocytic trafficking to lysosomes for degradation is a major APP clearance pathway that is differentially regulated by APOE isoforms
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) APOE , ARMDS2 , SBHD , AD2
    Susceptibility
  • putative susceptibility factor (epsilon 4 allele) for agressive multiple sclerosis, for early-onset coronary heart disease and Alzheimer's diseases (AD2)
  • susceptibility factor (epsilon 2/3/4 allele) for dementia (in old age)
  • susceptibility for AMD (age related macular dystrophy) (e2/e2 allele increased risk)
  • suceptibility (epsilon 2 allele) to frontotemporal dementia and to myocardial infarction
  • susceptibility to Alzheimer disease 2 (AD2)
  • to ischemic heart disease
  • to cerebral amyloid angiopathy and age-related cognitive decline during normal ageing
  • Variant & Polymorphism SNP , other
  • (-219G) associated with increased optic nerve damage in primery open angle glaucoma
  • epsilon 2 allele by mother correlated with Smith-Lemli-Opitz severe form
  • combinations of SNPs in APOE and LPL identify subgroups of individuals at substantially increased risk of ischemic heart disease
  • APOE haplotypes common, found to be significantly associated with AMD, G-G-G-G-epsilon2, T-C-G-G-epsilon3 and T-G-A-G-epsilon4
  • risk estimate of developing AD for individuals with two copies of the apoE4 allele (&
  • 8764;2p100 of the population) is &
    8764;60p100 by the age of 85, and for those with one copy of the apoE4 allele (&
    8764;25p100 of the population) &
    8764;30p100, but the lifetime risk of AD for those with two copies of the apoE3 allele is &
    8764;10p100 by the age of 85
  • APOE4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing
  • Candidate gene
    Marker
  • APOE genotyping may be helpful in diagnosing AD especially in patients presenting with atypical features or early age of onset of dementia
  • Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativealzheimer
    pharmacological intervention with small molecules that disrupt apoE4 domain interaction is a potential therapeutic approach for apoE4-carrying AD subjects
    ANIMAL & CELL MODELS
  • apoE4 causes age- and Tau-dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice (
  • young Apoe4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex