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Page 4 of 7 Leon et al. Neuroimmunol Neuroinflammation 2018;5:30 I http://dx.doi.org/10.20517/2347-8659.2018.26

A ApoE4 binding to LDL receptor with increased B ApoE4 binding affinity to LDL receptor
affinity causing AD pathology
decreases if a peptide is introduced
acting as an competitive antagonist
Competitive antagonist
ApoE2 is protective
ApoE4 from AD peptide blocking ApoE
from binding to the LDL
ApoE4 receptor may help
potentially to
ApoE4 has a 50 fold prevent or treat
increased affinity compared AD pathology
to ApoE2

LDL receptor Peptide ultimately blocks
LDL receptor the signaling and
endocytosis pathway
LDL receptor

Cell membrane Cell membrane

Figure 1. (A) ApoE4 has a 50 fold increased binding affinity to LDL receptor compared to ApoE2 (B). A novel approach is to create a
peptide targeting the ApoE LDLR binding domain. This peptide can work as a competitive antagonist for patients who are ApoE4 carriers.
Blocking the effect of ApoE4 binding affinity can help create a more ApoE2-like structure. ApoE2 is known to be protective in AD

moting degradation of Aβ. In addition, ApoE2 carriers have increased dendritic outgrowth, which enhances
the formation of new synapses and can protect against AD synaptic deterioration [34,39] . Further, ApoE2 pro-
tected cultured cells most effectively, compared to the other ApoE isoforms, from oxidative stress-induced
death in vitro . The cysteine to arginine substitution at position 158 in ApoE2 makes ApoE2 more stable to
[40]
thermal and chemical denaturation, compared to ApoE3 and ApoE4. Moreover, the cysteine residue at posi-
tion 112 creates a lesser chance to exhibit domain interactions relative to ApoE4 [34,41,42] . It has been suggested
that the development of drugs that can prevent the domain interaction of ApoE4 and convert ApoE4 to a
more ApoE3/ApoE2-like structure may be beneficial for individuals with neurodegenerative disorders. In ad-
dition, a peptide blocking the 135-150 N-terminal region may create a more ApoE2-like structure, as ApoE2
has decreased affinity for the LDLR. Given that ApoE2 carriers have a lower risk and delayed age of onset
of AD compared to E3 and E4 carriers [11,34,43] , it would stand to reason that creating a more ApoE2 structure
can be beneficial for treating AD rather than using ApoE E3 or ApoE4 structures.

CONCLUSION
Currently approximately 5.1 million Americans are affected with AD and the number is expected to triple
by 2050. Further there are no truly effective disease-modifying therapies for AD. ApoE4 is known to play
a major role not only in AD, but also atherosclerosis, CAA, tauopathies, dementia with Lewy bodies, and
stroke. Approximately the allele frequencies of E2, E3, and E4 in the human population are 7%, 78%, and
14%, respectively. ApoE genotypes have different affinities for LDLR, with ApoE2 having the weakest bind-
ing to LDLR at ApoE3 > ApoE2) [6,8,11,13,16,43-45] . We suggest that a peptide targeting the ApoE LDLR binding
domain may work as a competitive antagonist for patients who are ApoE4 carriers, in effect creating a more
ApoE2-like structure [Figure 1].

Creating a more ApoE2-like structure may be associated with greater likelihood of survival to advanced