RESEARCH: ALZHEIMERS
FOLDING PROJECT #18245 PROFILE

This project explores how changes in the ApoE protein might affect Alzheimer's disease. ApoE comes in different versions, some linked to a higher risk of Alzheimer's while others seem protective. The researchers use computer simulations to study how these different versions move and interact, hoping to understand their role in the disease and potentially develop new treatments.

Note: This TLDR is a simplication and may not be 100% accurate.

Alzheimer's disease is a significant cause of death in the USA and there are no effective treatments to halt or reverse disease progression.

Genetic polymorphisms (changes to the amino acids that comprise the protein) in apolipoprotein E (ApoE) are one of the strongest predictors of Alzheimer’s disease.

There are three dominant alleles (versions) of ApoE that are found in humans.

Each ApoE allele differs only by a single amino acid substitution.

ApoE3 is most common and carries a neutral risk for AD.

Carriers of ApoE2 (R158C) appear protected from Alzehimer's disease, whereas ApoE4 (C112R) carriers are 12-fold more likely to develop Alzheimer's disease.

Finally, a recent variant in ApoE3, ApoEchristchurch (R136S) has emerged which also appears to protect from Alzheimer's disease.

How these mutations in ApoE contribute to Alzheimer's disease, as well as how mutations in ApoE impact ApoE function, remains unclear. It is clear that ApoE isoforms can protect from Alzheimer's, suggesting that ApoE targeted therapeutics may be a means of reversing or preventing Alzheimer's disease progression.

Here, we will simulate how one varaiants of ApoE move in solution.

We hope these simulations will lead to a better understanding of how ApoE contributes to Alzheimer's disease. In our previous projects we simulated ApoE variants in the amber03 force field with the tip3p water model.

In our recent work, we have found that the amber99sb*-ILDN force field with tip4pd water does a reasonably good job of recapitulating appropriate protein dynamics for both disordered and ordered proteins.

Here, we apply these findings to ApoE4 to see if these simulations yield ensembles that more closely resemble experimental findings.

---

Alzheimer's disease

A progressive neurodegenerative disorder affecting memory, thinking and behavior.

Alzheimer's disease is a serious brain disorder that causes memory loss, thinking problems, and changes in personality. It is the most common cause of dementia, a group of disorders that affect cognitive function. There are currently no effective treatments to cure Alzheimer's disease.

---

Genetic polymorphisms

Variations in DNA sequences among individuals.

Genetic polymorphisms are variations in the DNA sequence that occur within a population. These variations can influence an individual's susceptibility to certain diseases, their response to medications, and other traits.

---

Apolipoprotein E (ApoE)

A protein that transports cholesterol and other lipids in the blood.

ApoE is a crucial protein involved in transporting cholesterol and fats throughout the body. It plays a role in various physiological processes, including lipid metabolism and brain function.

---

Alleles

Alternative forms of a gene.

Alleles are different versions of the same gene. For example, a gene for eye color might have alleles for blue eyes, brown eyes, or green eyes.

---

Amino acid substitution

A change in one amino acid in a protein sequence.

Amino acid substitution is a type of genetic mutation where one amino acid is replaced by another in a protein. This can alter the protein's function and structure.

---

ApoE2

A variant of apolipoprotein E that appears to protect against Alzheimer's disease.

ApoE2 is a specific form of apolipoprotein E that has been linked to a reduced risk of developing Alzheimer's disease. It may play a role in protecting brain cells from damage.

---

ApoE4

A variant of apolipoprotein E that increases the risk of Alzheimer's disease.

ApoE4 is a form of apolipoprotein E associated with an increased likelihood of developing Alzheimer's disease. It may contribute to the accumulation of amyloid plaques in the brain, a hallmark of the disease.

---

ApoE3

The most common variant of apolipoprotein E.

ApoE3 is the most prevalent form of apolipoprotein E. It has a neutral effect on Alzheimer's disease risk.

---

ApoEchristchurch

A recent variant of apolipoprotein E that appears to protect against Alzheimer's disease.

ApoEchristchurch is a newly identified variant of apolipoprotein E associated with reduced risk of Alzheimer's disease. It may offer insights into potential therapeutic targets for the disease.

---

Amber03 force field

A set of parameters used to describe the interactions between atoms in a molecular simulation.

Amber03 force field is a computational model used to simulate the behavior of molecules. It defines how atoms interact with each other based on their chemical properties.

---

Tip3p water model

A model of water molecules used in molecular simulations.

Tip3p water model is a representation of water molecules in computer simulations. It captures the essential properties of water, allowing researchers to study its interactions with other molecules.

---

Amber99sb*-ILDN force field

An advanced set of parameters used to describe the interactions between atoms in a molecular simulation.

Amber99sb*-ILDN force field is an improved model for simulating protein structures and dynamics. It provides more accurate representations of protein properties compared to older force fields.

---

Tip4pd water model

A model of water molecules used in molecular simulations.

Tip4pd water model is a refined representation of water molecules used in computer simulations. It offers better accuracy for simulating water properties compared to earlier models.