RESEARCH: ALZHEIMERS
FOLDING PROJECT #18223 PROFILE

This project looks at how different versions of a protein called ApoE affect Alzheimer's disease. Some versions of ApoE seem to protect against the disease, while others increase risk. Scientists are using computer simulations to understand how these different ApoE versions work and hope 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 disease affecting memory and cognitive function.

Alzheimer's disease is a serious brain disorder that causes memory loss, thinking problems, and changes in behavior. It is the most common cause of dementia, a group of symptoms affecting thinking, remembering, and reasoning.

Apolipoprotein E (ApoE)

A protein that plays a role in lipid transport and cholesterol metabolism.

Apolipoprotein E is a protein found in the blood that helps carry fats around the body. It's involved in many important processes, including transporting cholesterol and other lipids to cells.

Genetic polymorphisms

Variations in the DNA sequence that can affect protein function.

Genetic polymorphisms are slight changes in our DNA sequence. These changes can sometimes alter how proteins work and may influence our risk for certain diseases.

ApoE4

A variant of Apolipoprotein E associated with an increased risk of Alzheimer's disease.

ApoE4 is a specific form of the ApoE protein that has been linked to a higher likelihood of developing Alzheimer's disease. It plays a role in how fats are transported and processed in the brain.

ApoE2

A variant of Apolipoprotein E associated with a reduced risk of Alzheimer's disease.

ApoE2 is another form of the ApoE protein that appears to lower the chances of developing Alzheimer's disease. It may have protective effects on brain health.

ApoE3

A common variant of Apolipoprotein E with a neutral risk for Alzheimer's disease.

ApoE3 is the most frequently occurring form of the ApoE protein. It doesn't significantly increase or decrease the risk of developing Alzheimer's.

ApoE Christchurch

A rare variant of ApoE3 associated with a protective effect against Alzheimer's disease.

ApoE Christchurch is a less common form of ApoE3 that has been found to potentially reduce the risk of developing Alzheimer's disease.

Alleles

Different forms of a gene.

Alleles are variations of a gene. We inherit two alleles for each gene, one from our mother and one from our father.