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
binds preferentially to HDL
-
-
-
34.15
299
primarily produced by astrocytes in the brain, but neurons can also produce APOE4 under stress conditions
2012
22615372
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
binds preferentially to very low-density lipoprotein (VLDL)
4
-
1223
34.2
317
-
2012
22615372
with two alternative stop codons
-
-
5515
-
-
liver
2012
22615372
also called APOEAS2
-
-
-
-
219
parotis, kidney, liver, lung, thymus, small intestine
2012
22615372
also called APOEAS1
antisense transcript
4
-
1316
-
343
-
2012
22615372
4
-
1165
-
317
-
2012
22615372
-
-
-
34.15
299
-
2012
22615372
at residues 112 or 158 having cysteines
protective for Alzheimer disease
4
-
1249
-
343
-
2012
22615372
4
-
1270
-
317
-
2012
22615372
EXPRESSION
Type
ubiquitous
expressed in
(based on citations)
organ(s)
System
Organ level 1
Organ level 2
Organ level 3
Organ level 4
Level
Pubmed
Species
Stage
Rna symbol
Digestive
liver
highly
Homo sapiens
Endocrine
adrenal gland
highly
Lymphoid/Immune
spleen
moderately
Nervous
brain
predominantly
Homo sapiens
Reproductive
female system
ovary
moderately
Respiratory
lung
moderately
Urinary
kidney
highly
Visual
eye
retina
moderately
tissue
System
Tissue
Tissue level 1
Tissue level 2
Level
Pubmed
Species
Stage
Rna symbol
Epithelial
barrier lining
retinal pigment epithelium (RPE)
cells
System
Cell
Pubmed
Species
Stage
Rna symbol
Lymphoid/Immune
macrophage
Homo sapiens
Nervous
astrocyte
Homo sapiens
Nervous
neuron
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
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
APOE4 allele drives atrophy to the medial-temporal lobe region in AD
has an intrinsic role in pericyte mobility, which is vital in maintaining cerebrovascular function
role for APOE in lipid accumulation and adipogenic differentiation in adipose tissue
APOE is a critical determinants of brain phospholipid homeostasis and the APOE4 isoform is dysfunctional in this process
is an essential anti-atherosclerotic glycoprotein involved in lipid metabolism
impaired autophagy may play a role in mediating the pathological effects of APOE4 in AD
negative role of the APOE4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age
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
APOE/PLTP interactions can be modulated by the conformation and lipidation state of APOE
APOE regulates the endosomal formation of PMEL amyloid fibrils
robust synchronized induction of KLF4 and APOE expression during differentiation of monocytes to macrophages, and KLF4 up-regulates APOE gene in a dose-dependent manner
MYLIP is an E3 ubiquitin ligase that targets LDLR for degradation, is a critical determinant of brain APOE metabolism and APP plaque biogenesis
SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of APOE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling
APOE4-carriers with dementia of the Alzheimers' type, and memory decline and olfaction, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediodisplay a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions
constitutional
 
 
--low
 
depletion of endogenous APOE in adipocytes severely impairs lipid accumulation, which is associated with an inability to initiate differentiation (pMID: 26201081)
Susceptibility
putative susceptibility factor (epsilon 4 allele) for agressive multiple sclerosis
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
to Coronary Heart Disease (CHD)
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
ApoE4 mutation was associated with the increased risk of CHD, while ApoE2 allele had a decreased risk of CHD
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
System
Type
Disorder
Pubmed
neurology
neurodegenerative
alzheimer
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
hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in Vegfa following injury
APOE4 reduces evoked hippocampal acetylcholine release in adult mice