The Effects of Increasing Lipidation of APoE4

on Neurodegeneration and Alzheimer’s Disease

Veronica Benedict

May 22, 2020

Table of Content
Abstract…. Pg 1

Introduction… Pg 1

Abstract

The role of the Apolipoprotein (APoE) in the pathology of Alzheimer's Disease has

become more prevalent in finding a cure for the disease. The three different isoforms of APoE,

APoE2, APoE3 and APoE4, each has its own effect on cognitive function, and the risk of

neurodegeneration from Alzhimer’s. However, scientists have found that the lipidation of the

proteins plays a major role in their function, increasing or decreasing the risk of Alzheimr’s

development. The APoE proteins provide targets for scientists to analyze their structures and

how the APoE proteins interact with the composition of the brain, and effects of changing the

makeup of these APoE proteins, specifically how the cognitive function and memory is

improved. In this study, the insight of the effects of increasing the lipidation of the APoE4

protein on Alzheimer's and cognitive function will be provided.

Introduction

Alzheimer's Disease is a very prevalent neurodegenerative disease that damages the

memory and other cognitive functions . As the most common form of dementia, the most

prominent sign of the disease is memory loss, however there are many other symptoms

including, confusion, dramatic behavioral changes and difficulty performing tasks such as

speaking or walking. Alzheimer’s Disease can be caused by a combination of factors, including

age, genetics, lifestyle, and environment. Age is an important factor, for, according to the

Alzheimer's Association, most patients with Alzheimer’s are over 65. Increasing age increases

the risk of developing Alzheimer’s. One’s genetics also plays a key role in the development of
Alzheimer's. The inheritance of the Apolipoprotein E4 (APoE4) allele increases the chances of

neurodegeneration in the brain, thus leading to Alzheimer’s. Lifestyle choices, such as an

unhealthy diet, a lack of exercise, and withdrawal from social engagement, can also increase the

risk of Alzhiemer’s, for the brain is not being stimulated to perform efficiently. Lastly, the

surrounding environment can also affect the chances of developing the disease. For instance,

according to Lewis O. J. Killin et al, exposure to heavy amounts of toxic metals and other

chemicals increases the risk of Alzhiemer’s.

To reiterate, genetics is a significant factor of the development of Alzhimer’s.

Specifically, the APoE protein is found to be the main “genetic factor” linked to the disease. The

APoE protein helps to maintain lipoproteins and amyloid-β (Aβ) peptide clearance in the brain.

Lipidation is an important process due to the importance of lipids and protein regulation in cell

function and growth, especially in the brain. Furthermore, Aβ peptide accumulation contributes

to amyloid plaques that are found in Alzhimer’s patients (Chia-Chen Liu et al) In addition, there

are three different isoforms of the APoE protein: APoE2, APoE3 and APoE4. Their different

functions affect their regulation of lipid binding and Aβ clearance. APoE2 is known as the

neuroprotective, for this isoform helps rescue Aβ deposition and increase clearance. The APoE3

isoform is more neutral and is the most common isoform, with a worldwide frequency of 77.9%,

according to Chia-Chen Liu et al. Finally, the APoE4 isoform is the neurodegenerative isoform

and the strongest risk factor for Alzheimer’s, for it increases Aβ deposition and impairs its ability

to bind to lipids, causing a decrease in lipidation. (Chia-Chen Liu et al) Therefore, it is important

to increase lipidation for the Apolipoprotein E-4 protein due to the effects of the three different

types of the Apolipoprotein E proteins, the connection between these isoforms and Alzheimer’s,

the effects of lipids on neurodegenerative diseases, and the potentiality of increasing lipidation.
Literature Review
Apolipoproteins (APoE) are found to be the most relevant genetic factor for Alzheimer’s

Disease. The mechanisms of these proteins impact the brain’s cognition and function as the

APoE “...is a major cholesterol carrier that supports lipid transport and injury repair in the brain.

APOE polymorphic alleles are the main genetic determinants of Alzheimer disease (AD) risk”

(Chia-Chen Liu et al, 2012) When inheriting the APoE alleles, one receives two alleles, one

allele from the father and the other from the mother. Typically, one will develop a variation of

the APoE3 (the most common allele), and inherit either APoE2 or APoE4. The different

combinations often determines the risk of Alzheimer’s, as the three different alleles, APoE2,

APoE3 and APoE4, each have different effects on cognition, which will be explained further

later. Additionally, Aβ metabolism is an important system that allows for Aβ proteins to be

broken down and secreted in order to avoid plaques and aggregation. The APoE proteins play a

major role in Aβ metabolism; “APOE genotypes strongly affect deposition of Aβ to form senile

plaques and cause cerebral amyloid angiopathy (CAA), two major hallmarks of amyloid

pathology in AD brains.” (Chia-Chen Liu et al, 2012) The process of Aβ metabolism is an

important mechanism that allows for clearance in the brain. Without this process, Aβ plaques

accumulate in the periphery, causing aggregation, leading to neurodegeneration.

Additionally, lipid binding plays a major role in cognition affected by the APoE protein.

These APoE proteins involve another class of proteins: lipoproteins. Lipoproteins are complexes

that allow for the transportation of lipids, regulating balance and function, and are primarily

made in the brain. “ApoE–lipoproteins bind to several cell-surface receptors to deliver lipids and

also to hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events that lead to
synaptic dysfunction and neurodegeneration in AD.” (Chia-Chen Liu et al, 2012) Once again, the

function of lipid binding is another mechanism of APoE that regulates Aβ clearance in the brain,

to prevent neurodegeneration. The consistent transport of lipids helps to clear the periphery and

maintain stable levels of lipids and Aβ peptides. Furthermore, lipid binding in APoE proteins

involves monomeric lipids, which can react with other lipids, binding due to the C-terminal

domain. These binding domains are often followed by other binding steps. (Carl Frieden et al,

2017) The process of lipid binding involves different domains that regulate the effectiveness of

the binding of lipids. One of the domains includes the C-terminal domain which contains the

major lipoprotein-binding sites, excluding the binding receptor. This presumably results in the

APoE only being partially lipidated. Another APoE domain is the N-terminal domain, which is

linked to the C-terminal domain. Similarly to the C-terminal domain, “The [N-terminal] domain

is responsible for the LDLR-binding, yet, in isolation, binds weakly to lipids” (Jianglei Chen, et

al, 2011) The different domains of the APoE affect the binding of the lipids, which consequently

affects the effectiveness of the transportation of lipids. If the lipoproteins were to bind with lipids

only in the C-terminal or N-terminal, the lipids may not bind as effectively, causing an

imbalance of lipids, leading to damage of cognition.

Moreover, these effects are overall determined by the type of APoE protein one has. To

reinforce, with its three different isoforms, each APoE isoform has different effects on the

cognitive function of the brain. Firstly, ApoE2 has been found as a neuroprotectant, however due

to the limited research on how it provides neuroprotection, the researchers, Long Wu and Liqin

Zhao, Ph.D, designed an experiment to examine differences at the molecular level. It was found

that the brains of individuals with the ApoE2 isoforms have the strongest profiles bio-

energetically, allowing it to provide neuroprotection. Furthermore, it was shown how when

comparing the different brains with the different isoforms, the mechanism of how ApoE2

provides the neuroprotection and benefits cognitive function is revealed. (Long Wu and Liqin

Zhao, 2016) Having an APoE2 allele will decrease the risk of developing Alzherimer’s, and

increase neuroprotective mechanisms to protect against neurodegeneration, or dementia in

general. Additionally, unlike the other two APoE proteins, APoE2 will provide improved

function to increase cognition in individuals.

The APoE3 protein is considered as to be the most common and more neutral protein, as

it does not provide neuroprotection nor cause neurodegeneration. Through the regulation of its

functions, “ApoE3 displays extensive domain interactions of salt-bridges and H-bonds, causing

shielding of the major LDLR-binding region by the [C-terminal] domain from binding to

receptors” (Jianglei Chen, et al, 2011) One of the mechanisms of APoE3 is the involvement of

the covalent interactions of the salt-bridges and H-bonds, which lead to lipids unable to bind to

the lipid receptor in the C-terminal domain. This allows for the lipids to instead remain lipidated,

which plays a vital role in cell signaling and regulation of the APoE protein function. Unlike

APoE2 and APoE4, the APoE3 mechanism allow for more neutral effects on cognition and

neurobehavior.

APoE4 is found to have neurodegenerative effects and is linked to Alzheimer’s as the

most likely genetic factor. APoE4 has clinically shown to advance neurodegeneration, increasing

the “...severity of cognitive decline, with a lower age of onset, and with altered response to AD

treatments.” (Long Wu and Liqin Zhao, 2016) As shown to be the commonly found genetic

factor of Alzhiemr’s, individuals with the APoE4 protein experience faster and more detrimental

affects causing neurodegeneration that those with APoE2 or APoE3. The APoE4 protein affects

many important mechanisms that occur in the brain, including Aβ deposition and domain to
domain interaction, leading to cognitive decline and neurodegeneration. Having the APoE4

protein causes “...[an] increased amount of Aβ including the more toxic oligomeric form found

in post-mortem AD brains. During disease progression, APOE ε4 exacerbates intra-neuronal Aβ

deposition and plaque deposition in the brain parenchyma…” (Yu Yamazaki, et al, 2016) Unlike

APoE2, APoE4 is unable to perform Aβ clearance successfully, leading to the Aβ to form as

toxic plaques that accumulate. This accumulation leads to the blocking of important pathways

and cerebral arteries, which damages cognitive function leading to neurodegeneration as seen

through the Alzheimer's Disease. Correspondingly, APoE4 also affects the domain-domain

interactions, which can be compared to APoE3. While APoE3 does bind to the C-terminal

domain, “APOE4 is unique in that it has increased propensity of domain-domain interactions that

reduces lipid binding to the C terminal domain leading to loss of stability and function. The

presence of Arg112 in APOE4 enhances the intramolecular interaction between its N-terminal

domain and the C-terminal domain via a salt bridge known as the APOE4 domain interaction. As

a result, APOE4 is typically hypolipidated…” (Tosha Williams et al, 2020) Hypolipidation,

where the lipoproteins are not completely lipidated leads, is a detrimental factor of APoE4. Since

the lipoproteins are less lipidated, they are not able to effectively continue performance of

critical functions that is needed for successful cognition and neurobehavior.

Lipidation of proteins, specifically APoE is important for cognitive function.

On a different note, the lipidation of proteins, specifically APoE, is essential for effective

cognitive function. Lipid transfer is essential for maintaining neurons to an extent. An increase in

lipid transfer and any impairment of lipid transports could lead to neurodegeneration and

damage. (Penelope J. Hallett et al, 2019) Having lipids transfer into the APoE protein is essential

for these lipids provide important roles that help proteins, including protection, energy storage,

signaling and structure. As these lipids provide continuously provide for the APoE proteins, the
APoE is able to carry out its function, which stimulates and improves cognition of the brain. This

can be seen with the APoE3 protein, where the protein is lipidated, enabling the protein to work

effectively, which causes the individual to have normal levels of cognition. Without proper

lipidation, the APoE may not work effectively.

With decreased lipidation, as seen with APoE4, the risk of neurodegeneration and

developing Alzheimer’s is increased. The lack of the transfer of lipids into the APoE4 causes the

protein to be unable to perform successfully in its functions, specifically regarding cognition and

memory. As lipidation decreases for the APoE4, “The effects… may result in reduced neuronal

protection or repair. Neuronal injury increases brain APOE levels, although the increase is not

immediate. The presence of an APOE4 allele decreases the brain’s neuronal reparative capacity

in AD patients.” (Rebeck, 2017) One of the neurodegenerative factors of the APoE4 includes its

hypolididated characteristics. Due to the lack of lipidation, the APoE is unable to successfully

perform its function, causing insufficiency in cognition and memory of the individual.

Additionally, the presence of the APoE4 inhibits the neuroprotective role the APoE protein plays

in the brain, causing a neurodegeneration, leading to Alzheimer’s.

Currently, several research regarding potential treatment plans for Alzhier’s is being

conducted. One of the more prominent methods related to the using of the APoE4 as a target fro

treatment. Since the APoE4 allele of the APoE protein has many factors that add up to its

neurodegenerative characteristics, there are different methods for targeting APoE4. Firstly, the

increasing of the expression of the Abca1 regulatory protein in the APoE4 has become a

potential method. ABCA1 is an important factor in lipidation of ApoE genes, and if increased,

could provide a potential treatment method for ApoE-4 isoforms.(Safieh, M., Korczyn, et al,

2019) Although the research is still recent, there have been findings related to the Abca1 and
APoE4, and how its expression can help decrease or eliminate the neurodegenerative effects of

the APoE4. With the Abca1, the APoE protein will be able to better perform cognitive tasks,

improving memory and reducing the risk of cognitive decline from Alzhiemr’s. Furthermore, as

the expression of Abca1 decreases Aβ accumulation,“...deficiency of Abca1 exacerbates

[amyloid responses] while overexpression of ABCA1 reduces the amyloid load in PDAPP

transgenic mice. [This supports] the hypothesis that ABCA1-mediated lipidation is crucial Aβ

clearance,” (Williams et al, 2020) With the expression of Abca1, the neurotoxic effects of

APoE4 will be reduced, allowing for improved cognitive levels and memory.

Another prominent method targeting APoE4 is the correction of the domain interactions

of the proteins to other molecules. “...[When] apoE4 is expressed in neurons under stress,

domain interaction is responsible for [breakdown] of… apoE4 into neurotoxic fragments.

Domain interaction-mediated apoE4 [breakdown] was found to result in mitochondrial

dysfunction in neurons. Small molecule structure correctors that interfere with this property and

convert apoE4 to an apoE3-like molecule have been reported to mitigate the neurotoxic effects”

(Suidan and Ramaswamy, 2019) Through the improvement of the domain interactions of APoE4,

more molecules will be able to interact and bidn with the APoE, allowing for the reduction of the

neurotoxicity of the APoE4. Additionally, through this method, the APoE4 will be made more

similar to the characteristics of the APoE3, allowing for more neutral effects relating to cognition

and memory.

Finally, one of the more promising methods that is being studied is the increasing of

lipidation of the hypolipidated APoE4. A key factor of this method accounts for the expression

of Abca1. As many studies have shown, “... a direct peptide activator of abca1, CS-6253, has …

[increased] lipidation of apoE4... suggesting that increasing apoE4 lipidation via Abca1
activation could overcome the pathological effects of the apoE4 allele (Suidan and Ramaswamy,

2019) Through the expression of Abca1 and the increasing of lipidation in the APoE4, this

method has the potential to decrease the risk of neurodegeneration caused by APoE4. Increasing

lipidation will allow for more molecules and lipids the APoE4 is deprived of to enter the protein

and provide for the APoE. Therefore, increasing lipidation through the expression of Abca1 will

decrease the chances of an individual developing Alzheimer’s. This will be further explained

below.

Data Collection

Part I:

The Study Purpose Results How did the How effective

study change were the results?
alter APoE4
pathways?

“ABCA1 To utilize CS- The Abca1 In this study, the The results of
Agonist 6253, which agonist, CS- researchers used this study
Reverses the would activate 6253, increased the CS-6253, showed to be
ApoE4- Driven Abca1, and Abca1 levels in which enabled effective, as the
Cognitive and examine the APoE4 mice, as Abca1, which is mice showed
Brain extent to which well as lipidation a major transport improved
Pathologies” it can affect the levels. These protein related to cognitive
(Anat Boehm- degree of levels were lipidation and function and
Cagana, Roni lipidation of unaffected in the homeostasis of memory.
Bara, Ori Liraza, APoE4 and APoE3 mice. lipoproteins. The Additionally,
John K. counteract the researchers although
Bielickib, Jan O. associated brain essentially performance
Johanssonc and and behavioral increased the levels of the
Daniel M. pathologies. lipidation APoE3 group
Michaelson, pathway of were higher, the
2016) APoE4 to APoE4 group
stimulate only differed by
lipidation and a small margin
change its of...
characteristics to
be more similar
to APoE3.

To examine how Showed that Through this The study

much the APoE plasma study, the showed that the
“Differential neuroprotective levels are lower researchers were CS-6253 is
Effects of apoE4 effects of the in APoE4 mice able to change effective to an
and Activation CS-6253 leads to than APoE3 the lipidation extent. The
changes in the mice. The Abca1 pathway of results indicated
of ABCA1 on levels and extent agonist, CS- APoE4 to be how cognitive
Brain and of lipidation of 6253, reverses more similar to function and
Plasma peripheral apoE4 the effects of APoE3 by using memory of those
and to APoE4 the CS-6253 with APoE4 can
Lipoproteins” corresponding (cognitive peptide to be improved and
(Anat Boehm- changes in the impairments, activate Abca1, be made similar
Cagan, Roni Bar, levels of APoE3. increases which would to APoE3, as the
lipidation and allow for results reveal
Dror Harats, decreases increased how the APoE4
Aviv Shaish, aggression). The lipoproteins in mice improved
agonist did not the APoE4 their
Hana Levkovitz,
have any effect protein to performance
John K. Bielicki, on APoE3 essentially levels from
Jan O. levels. “become” or be before and after
more similar to the CS-6253.
Johansson, and
APoE3.
Daniel M.
Michaelson,
2016)
“Novel Apo E- Examining the CS-6253 In this study, the The results of
Derived ABCA1 effects of CS- mediated CS-6253 peptide this study show
Agonist Peptide 6253 on Abca1 cholesterol and was used on how cognitive
(CS-6253) dynamics and Aβ levels, Abca1 to create function was
Promotes ability to create therefore lipoproteins improved with
Reverse lipoproteins by mediating without effecting the CS-6253,
Cholesterol using in vitro lipidation in APoE4 directly. and other effects
Transport and models. APoE4. The This meant that of APoE4 were
Induces agonist also its effects had reversed by the
Formation of stimulates the increased effects of the
preβ-1 HDL In production of cognitive CS-6253,
Vitro” (Anouar HDL particles, a function, including high
Hafiane, John K. major however the cholesterol
Bielicki, Jan O. lipoprotein. APoE4 protein levels, allowing
Johansson, and itself was for an increase in
Jacques Genest, unaffected. lipidation.
2015) Additionally, the
effects of the
CS-6253
inhibited certain
effects of
APoE4,
including its
high cholesterol
levels. With
these high
cholesterol
levels, the
APoE4 protein is
unable to
transport further
lipids through its
membrane,
increasing its
hypolipidation.
However, with
CS-6253, these
effects were
reversed.

To reveal the The Abca1 Through this The results of

effect of Abca1 agonist, CS- study, the CS- this study reveal
“Abca1 deficiency on 6253, decreased 6253 activated how the CS-
 phenotype in Aβ accumulation Abca1 to 6253 is an
mice expressing in APoE4 mice, decrease Aβ effective method
human ApoE3 but not in accumulation, to use to reverse
Deficiency and APoE4. APoE3 mice. which occurs in the decreased
Affects The agonist also those with the lipidation
Alzheimer's improved APoE4 proteins, mechanism of
cognitive therefore the CS- APoE4. With
Disease-Like performance in 6253 was CS-6253, the
Phenotype in APoE4 mice and interfering with transport of
Human ApoE4 increased this mechanism. lipids can be
lipidation. Additionally, as activated,
But Not in Aβ clearance allowing an
ApoE3-Targeted was stimulated, increase in
Replacement the APoE4 was lipidation, which
changing in the improves
Mice” (Nicholas sense that it was cognitive
F. Fitz, Andrea more similar to function, as seen
APoE3. with the study.
A. Cronican,
Muzamil
Saleem, Abdul
H. Fauq, Robert
Chapman Iliya
Lefterov, and
Radosveta
Koldamova,
2012)

Part II (Analysis):

Rationale:

In order to determine an effective method to reverse the effects of APoE4, it is important

to find information from previous case studies that have shown the effects of the drug, CS-6253,

using a qualitative research design. Furthermore, to collect data, an experimental data collection

method would be most effective to study the effects of the independent variable, CS-6253, on the

dependent variable, APoE4. To collect this data, using the data collection method of meta-

analysis was the most appropriate method due to the limited resources that the researcher
physically has. However the researcher did have access to the many studies that have been

conducted over the years, which made meta-analysis the most feasible method. By analyzing

raw, reliable data from four case studies, key results from each of the studies were found. The

studies all collectively have similar methodologies and results throughout their trials. Similarly,

their background information and purposes are also almost complementary, if not the same.

Additionally, it was important to find studies that well explained the importance of finding a

method to treat APoE4 in a manner that reverses its effects, but does not affect the genotypic or

phenotypic levels of APoE3 This allowed for the comparison of the effects of CS-6253 on

APoE4 shown through all the case studies to determine how effective CS-6253 is in reversing

the detrimental effects of APoE4.

Analysis

The four studies analyzed all had similar results and processes used by throughout their

processes. As shown in the table above, the authors of three of the four studies were able to use

the CS-6253 peptide to alter its levels to match APoE3 levels, while also not affecting the

APoE3 proteins in the mice. The study conducted by Hafiene et. al. however did not examine the

effects of CS-6253 on APoE3. Through these studies, as well as from previous research, it was

proven that one of the major differences between the APoE3 protein and APoE4 protein is their

lipidation levels. However, this difference was adjusted by the CS-6253 peptide to be more

similar to APoE3. This not only led to lipidation levels being similar among the two proteins, but

also Aβ deposition. Most importantly, cognitive levels of the mice with APoE4 protein increased

and these mice had better cognitive function and spatial learning abilities.

Additionally, among all four studies, the findings were consistent and there were major

no outliers in the data. This illustrates how CS-6253 poses as a viable method that could be used
to target APoE4 in Alzhimer’s patients. Nevertheless, these studies also had a few risks involved

using CS-6253. Specifically, in the study, “ABCA1 Agonist Reverses the ApoE4- Driven

Cognitive and Brain Pathologies,” the authors, Boehm-Cagana et. al., state the possibility of risks

being involved in the study since they did not completely know the full mechanism of the

peptide, and how the APoE4 protein could be affected. Although this risk created some

uncertainty at the beginning of the study, the authors were still successful in completing their

study and they acquired results that correlated with the findings of the other three studies.

Conclusion

The results of these studies show the extent to how successful CS-6253 is in altering

APoE4 to correspond to APoE3 levels. Overall, using the CS-6253 peptide is a viable method

that could be used to target APoE4 in Alzhiemer’s patients to increase its lipidation, improve

cognitive performance, and decrease Aβ accumulation, to allow the protein to have similar

effects to APoE3. This ultimately improves cognitive function and spatial learning. Additionally,

lipidation is generally an important factor in APoE, which was heavily expressed throughout

several literature review articles. This was proven in these studies as well, as the mice with the

APoE4 protein had improved cognitive function as they received the CS-6253 peptide compared

to the control APoE4 mice. This again illustrates how important this method is and its possibility

of being used to treat Alzhiemer’s patients. Using peptides such as CS-6253 and finding more

treatment methods that increase lipidation long term is an important goal to find for people

suffering from Alzheimer’s Disease. With increased lipidation, cognitive function and memory is

improved, and the brain is further stimulated to improve its activity. With these results, scientists

in the future will be able to continue to develop treatment methods to treat APoE4 and
Alzheimer’s patients, and eventually a cure, to help decrease the amount of people suffering

from the disease.

Conclusion

Alzhiemer’s, the most common form of dementia, is a widespread disease, affecting

almost 44 million people worldwide. Although caused by a variety of factors, the impact of the

APoE4 protein in the development of the Alzheimer's Disease has been proven to be one of the

most unparalleled genetic risk factors. Over the years, many studies have shown the significance

of the APoE protein and how it affects the cognitive function of individuals with APoE4.

However, more recently, an increasingly amount of studies have shown that the decreased

lipidation in the APoE4 causes its neurodegenerative characteristics, leading to Alzhiemr’s.

Furthermore, studies and trials have also shown that increasing the lipidation of the APoE

improves cognitive function in mice, proving that increasing lipidation of APoE4 is an effective

method to continue to study. In summary, it is important to continue further research into the

cure of Alzhimer’s Disease to help millions of people affected.

 References

Abca1 Deficiency Affects Alzheimer's Disease-like Phenotype in Human Apoe4 But Not in

Apoe3-targeted Replacement MiceNicholas Fitz-Andrea Cronican-Muzamil Saleem-

Abdul Fauq-Robert Chapman-Iliya Lefterov-Radosveta Koldamova -

https://www.jneurosci.org/content/32/38/13125

"ApoE3 displays extensive domain interactions of salt-bridges and H-bonds, causing shielding of

the major LDLR-binding region by the [C-terminal] domain from binding to receptors"

(Jianglei Chen, et al, 2011)

Boehm-Cagan, A., Bar, R., Liraz, O., Bielicki, J. K., Johansson, J. O., & Michaelson, D. M.

(2016). ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies.

Journal of Alzheimer's disease : JAD, 54(3), 1219–1233. https://doi.org/10.3233/JAD-

160467
Boehm-Cagan, A., Bar, R., Harats, D., Shaish, A., Levkovitz, H., Bielicki, J. K., Johansson, J. O.,

& Michaelson, D. M. (2016). Differential Effects of apoE4 and Activation of ABCA1 on

Brain and Plasma Lipoproteins. PloS one, 11(11), e0166195.

https://doi.org/10.1371/journal.pone.0166195

Frieden, C., Wang, H., & Ho, C. (2017). A mechanism for lipid binding to apoE and the role of

intrinsically disordered regions coupled to domain-domain interactions. Proceedings of

the National Academy of Sciences of the United States of America, 114(24), 6292–6297.

https://doi.org/10.1073/pnas.1705080114

Hafiane, A., Bielicki, J. K., Johansson, J. O., & Genest, J. (2015). Novel Apo E-Derived ABCA1

Agonist Peptide (CS-6253) Promotes Reverse Cholesterol Transport and Induces

Formation of preβ-1 HDL In Vitro. PloS one, 10(7), e0131997.

https://doi.org/10.1371/journal.pone.0131997

Lipid and Immune Abnormalities Causing Age-dependent Nuerodegeneration and Parkinson's

Disease. Penelope Hallett-Simone Engelender-Ole Isacson -

https://www.ncbi.nlm.nih.gov/pubmed/31331333

Liu, C. C., Liu, C. C., Kanekiyo, T., Xu, H., & Bu, G. (2013). Apolipoprotein E and Alzheimer

disease: risk, mechanisms and therapy. Nature reviews. Neurology, 9(2), 106–118.

https://doi.org/10.1038/nrneurol.2012.263

Rebeck G. W. (2017). The role of APOE on lipid homeostasis and inflammation in normal

brains. Journal of lipid research, 58(8), 1493–1499. https://doi.org/10.1194/jlr.R075408

Safieh, M., Korczyn, A.D. & Michaelson, D.M. ApoE4: an emerging therapeutic target for

Alzheimer's disease. BMC Med 17, 64 (2019). https://doi.org/10.1186/s12916-019-1299-

4
Targeting Apolipoprotein E For Alzheimer's Disease: An Industry PerspectiveGeorgette Suidan-

Gayathri Ramaswamy - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539182/

Williams, T., Borchelt, D.R. & Chakrabarty, P. Therapeutic approaches targeting Apolipoprotein

E function in Alzheimer's disease. Mol Neurodegeneration 15, 8 (2020).

https://doi.org/10.1186/s13024-020-0358-9

Wu, L., & Zhao, L. (2016). ApoE2 and Alzheimer's disease: time to take a closer look. Neural

regeneration research, 11(3), 412–413. https://doi.org/10.4103/1673-5374.179044

Yamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016). Apolipoprotein E as a Therapeutic

Target in Alzheimer's Disease: A Review of Basic Research and Clinical Evidence. CNS

drugs, 30(9), 773–789. https://doi.org/10.1007/s40263-016-0361-4