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sion of LDLR decreases ApoE levels in the brain, while LDLR deficient mice have increased ApoE brain ac-
cumulation [24,25] . Further, LDLR overexpression elevates uptake of Aβ in astrocytes. Conversely, deletion of
[26]
LDLR has an opposing effect . Upon culturing brain sections with Aβ plaques with murine astrocytes, Aβ
[27]
was taken up and degraded via LDL receptor or LDL receptor related protein . ApoE contains 299 residues
and was identified as a main component of lipoproteins in plasma. It has been established that lysine and
arginine residues situated between ApoE residues 136 and 150 interact directly with acidic residues in the
ligand binding domain of LDLR. In addition, full receptor binding activity requires arginine at position 172
located at the hinge region that connects the N- and C-terminal domains. ApoE3 and ApoE4 bind to LDL
[28]
receptors with high affinity, but the binding of ApoE2 is 50- to 100-times weaker . These data suggest that
ApoE4 confers the highest risk for AD pathology due to its increased affinity for LDLR.

Recent research has shown that ApoE binding to ApoE receptors increases transcription of Aβ through
activation of the mitogen activated protein (MAP) kinase signaling pathway involving dual leucine-zipper
kinase (DLK). In fact, ApoE binding to cell-surface ApoE receptors activates DLK. The levels of Aβ potency
production increase according to the different human ApoE isoforms (ApoE4 > ApoE3 > ApoE2). Specifi-
cally, when ApoE binds to ApoE receptor, DLK is activated. DLK will then activates dual specificity mitogen-
activated protein kinase kinase 7 (MKK7) and extracellular signal-regulated protein kinase (ERK) 1/2 MAP
kinases. Further more, activated ERK1/2 induces cFos phosphorylation, that will eventually stimulate the
transcription factor activation protein (AP)-1. Transcription factor AP-1 will enhance transcription of APP
[29]
and thereby increase Aβ levels . Therefore, a peptide or antibody blocking the interaction between LDLR
and the ApoE binding site may potentially decrease the MAP kinase cascade and APP transcription, ulti-
mately leading to a decrease in Aβ production. Previous research demonstrated that the monoclonal anti-
[30]
body 1D7 is specific for human ApoE and blocks binding of lipid-associated ApoE to LDLR . 2E8 mono-
[31]
clonal antibody also binds to ApoE and prevents ApoE-mediated binding of lipoproteins to the LDLR .

APOE2-LIKE PROPERTIES AND BENEFITS
Although ApoE2 known to cause type III hyperlipoproteinemia, the E2 allele is known for being protective
against the development of late onset Alzheimer’s disease (LOAD) compared to the common E3 and E4 al-
lele as exemplified by a delayed age of onset and a greater likelihood of survival to advanced age. A cross-sec-
tional multimodal neuroimaging approach has shown ApoE2 to be protective in the aged brain. In addition,
the ApoE2 allele appears to have a relatively selective effect on reduced accumulation of amyloid pathology
in the aged brain [32-34] . It has been reported that ApoE2 can promote type III hypercholesterolemia, leading to
increased cardiovascular disease. However, studies demonstrate that ApoE4 knock-in mice have lower than
normal brain cholesterol concentrations even though peripheral cholesterol levels are increased. This finding
suggests that brain ApoE metabolism is distinct from that in the plasma. Moreover, the blood-brain barrier
(BBB) effectively prevents the exchange of brain tissue and plasma lipoproteins. Thus, peripheral cholesterol
cannot cross the BBB and enter the brain. Brain cholesterol is mainly synthesized in situ and provided by de
novo synthesis, primarily by astrocytes and oligodendrocytes [11,32-35] .

ApoE2 is associated with slower cognitive decline, milder Aβ pathology, and less neurodegeneration com-
pared to ApoE3 and ApoE4. Older individuals who are ApoE2 carriers display superior verbal learning
abilities, and faster processing of information. Possession of at least one copy of the ApoE2 allele has demon-
strated a slower decline in episodic memory [34,36] . All isoforms of ApoE can modulate Aβ clearance. However,
aging APP transgenic mice expressing human ApoE2 also have the slowest rate of production of Aβ oligo-
[37]
mers with neuritic plaque formation compared to ApoE3 and ApoE4 mice .
Rats expressing human ApoE2 have been shown to be protected from apoptotic death of cortical neurons in-
[38]
duced by Aβ peptides . ApoE2 mice are also more effective in clearing Aβ from the bloodstream and pro-