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Page 2 of 7 Leon et al. Neuroimmunol Neuroinflammation 2018;5:30 I http://dx.doi.org/10.20517/2347-8659.2018.26

INTRODUCTION TO APOE
As life expectancies increase, more elderly patients are diagnosed with Alzheimer’s disease (AD). AD brain
exhibits close to 50% neuron loss in the cortex. Genome-wide association studies (GWAS) have identified the
[1,2]
apolipoprotein E (ApoE) gene as a risk factor for AD . It has been found that there is a strong correlation
between ApoE4 carriers and higher levels of amyloid pathology. However, individuals who do not carry the
[3-6]
ApoE4 allele seem to demonstrate fewer AD disease processes or other neurodegenerative disorders .
The human ApoE gene is encoded on chromosome 19. ApoE is a 34-kDa protein consisting of 299 amino
acids and is constitutively expressed in astrocytes, microglia, vascular smooth muscle cells, and choroid
plexus while neurons typically generate ApoE under stress conditions. Through mRNA studies it has been
demonstrated that the liver is the major producer of ApoE, followed next by the brain. The receptor-binding
domain of ApoE is located within amino acids 136-150 of the N-terminal region. There are three different
human isoforms of ApoE (ApoE2, ApoE3, and ApoE4) which differ by only 2 amino acids at sites 112 and
158. ApoE2 has cysteines located at both sites, ApoE3 has a cysteine at site 112 and arginine at site 158 while
[7,8]
ApoE4 has arginines at both sites . The heterogeneous nature of the three isoforms is secondary to ge-
[9]
netic polymorphisms . It has been shown that there is a linear reduction in brain hippocampal volumes by
magnetic resonance imaging (MRI) scans according to ApoE genotype in the following hierarchy: ApoE4 <
ApoE3 < ApoE2. In AD patients, ApoE4 carriers had significantly smaller hippocampal volume compared
to ApoE2 carriers. This study used several well-characterized cohorts to analyze the neuroanatomic effect of
[10]
ApoE on the left and right hippocampal volumes . In addition, research has shown that the E4 allele is also
a risk factor for atherosclerosis, human immunodeficiency virus (HIV) disease progression, cerebral amyloid
[11]
angiography (CAA), tauopathies, dementia with Lewy bodies, and Parkinson’s disease .

APOE4 MECHANISM
[12]
ApoE4 increases the risk of developing AD by 4-fold with one allele and 14-fold with two alleles . The
approximate allele frequencies of E2, E3, and E4 in the human population are 7%, 78%, and 14%, respec-
tively [6,13] . Moreover, it has been shown through histological analyses of AD brains that ApoE is co-deposited
[14]
with amyloid-beta (Aβ) in amyloid plaques . It has also been revealed that Aβ clearance is faster in ApoE3
[15]
transgenic mice versus ApoE4 transgenic mice . This is likely because ApoE4 has an altered structure com-
pared with ApoE2 or ApoE3, which alters its function. Therefore, understanding the structural properties of
ApoE and its isoforms is vital to creating a prophylactic or therapeutic treatment. Research has shown that
competition assays with ApoE4, ApoE3, and Tau revealed that ApoE4 inhibits Tau degradation. In addition,
a single nucleotide polymorphism rs429358 defines ApoE4 and is located within exon 4 of apolipoprotein
E. In regard to ApoE4, the arginine at position 112 directly influences arginine-61, which allows for domain
interaction with glutamine-255. In addition, this bulky charged arginine residue destabilizes the N-terminal
helix bundle domain, inducing helix shortening between amino acids 12 and 20 of the N-terminal domain
and residues 204 and 210 of the C-terminal domain which reduces ApoE4 ability to form tetramers. This re-
sults in ApoE4 binding preference for very low-density lipoprotein (VLDL) [16-20] .

APOE AND THE LOW-DENSITY LIPOPROTEIN RECEPTOR INTERACTION
LDLR is one member of a family of seven core LDL receptor-related proteins (LRPs), which also includes
LDLR-related protein 1 (LRP1), the VLDL receptor (VLDLR), megalin (LRP2), apolipoprotein E receptor 2
(ApoER2), and LRP4. All LDL receptor family members share structural properties that allow interaction
[21]
with ApoE . In addition, LDL receptor family members contain a transmembrane domain which can be
endocytosed, proteolytically processed, and interact with cell proteins, including direct interaction with
[22]
(amyloid precursor protein) APP . LDLR, VLDLR, LRP, and ApoER2 are present in a number of brain cells
[23]
including astrocytes, microglia, neurons, and oligodendrocytes . It has also been reported that overexpres-