RESEARCH: ALZHEIMERS
FOLDING PROJECT #18222 PROFILE

This project looks at how different versions of a protein called ApoE might affect Alzheimer's disease. Some versions of ApoE seem to protect against the disease, while others increase the risk. Researchers are using computer simulations to understand how these different ApoE versions work and hope to use this knowledge to develop new treatments for Alzheimer's.

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. P18215- Apolipoprotein E4, highly associated with Alzheimer's disease severity and early onset. p18218- Apolipoprotein E3, Christchurch.

A rare isoform of ApoE which seems to be protective from familial Alzheimer's disease. p18219- Apolipoprotein E3, The most common isoform of ApoE.

Risk neutral for Alzheimer's disease and the baseline comparator for our studies. p18220- Apolipoprotein E2, a slightly protective isoform of Apolipoprotein E with respect to Alzheimer's disease.

ApoE2 carriers have an increased risk of hyperproteinemia. p18221- Apolipoprotein E3(Serine).

Many of our experiments in the wet lab utilize this variant of E3 as it is chemically more ammenable to our studies.

We are exploring the impact of this experimental mutation on the underlying conformational ensemble of ApoE3 (p18219). p18222- Apolipoprotein E3, Christchurch (Serine).

Many of our experiments in the wet lab utilize this variant of E3 Christchurch as it is chemically more ammenable to our studies.

We are exploring the impact of this experimental mutation on the underlying conformational ensemble of ApoE3Ch (p18218). p18223- Apolipoprotein E2(Serine).

Many of our experiments in the wet lab utilize this variant of E2 as it is chemically more ammenable to our studies.

We are exploring the impact of this experimental mutation on the underlying conformational ensemble of ApoE2 (p18220).

Alzheimer's disease

A progressive neurodegenerative disorder characterized by memory loss and cognitive decline.

Alzheimer's disease is a serious brain condition that causes problems with memory, thinking, and behavior. It gradually worsens over time, affecting people's ability to function independently.

ApoE

Apolipoprotein E

ApoE is a protein that plays a role in transporting fats (lipids) in the body. Different variations of ApoE can affect a person's risk of developing Alzheimer's disease.

Polymorphisms

Variations in DNA sequence among individuals.

Polymorphisms are slight differences in people's DNA sequences. These variations can influence traits and susceptibility to diseases like Alzheimer's.

Alleles

Different versions of a gene.

Alleles are alternative forms of a gene. For example, a person might inherit one allele for blue eyes and one allele for brown eyes.

Amino Acid Substitution

A change in one amino acid within a protein sequence.

Amino acids are the building blocks of proteins. A substitution occurs when one type of amino acid is replaced by another in a protein's structure.

ApoE2

Apolipoprotein E Isoform 2

ApoE2 is a variant of the ApoE protein that is associated with a reduced risk of Alzheimer's disease.

ApoE4

Apolipoprotein E Isoform 4

ApoE4 is a variant of the ApoE protein that significantly increases the risk of developing Alzheimer's disease.

ApoE3

Apolipoprotein E Isoform 3

ApoE3 is the most common variant of the ApoE protein and has a neutral risk for Alzheimer's disease.

Hyperproteinemia

A condition characterized by elevated levels of protein in the blood.

Hyperproteinemia is a medical term for high levels of protein in the bloodstream. It can sometimes be associated with certain diseases or conditions.