RESEARCH: ALZHEIMERS
FOLDING PROJECT #18216 PROFILE

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

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. 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).

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Alzheimer's disease

A progressive neurodegenerative disease causing cognitive decline.

Alzheimer's disease is a serious brain disorder that slowly destroys memory and thinking skills. It is the most common cause of dementia, affecting millions worldwide. Currently, there are no cures for Alzheimer's, but treatments can help manage symptoms.

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Apolipoprotein E (ApoE)

Apolipoprotein E is a protein that helps transport fats (lipids) in the blood.

ApoE is a crucial protein involved in transporting fats throughout the body. It plays a role in various processes, including brain health and cholesterol regulation. Certain variations of ApoE can increase or decrease the risk of developing Alzheimer's disease.

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Genetic Polymorphisms

Variations in DNA sequence that can affect protein function.

Genetic polymorphisms are slight differences in our DNA sequences. These variations can influence how our bodies process information and respond to medications or environmental factors. They play a significant role in understanding disease susceptibility and individual responses to treatment.

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Alleles

Different forms of a gene.

Alleles are alternative versions of the same gene. We inherit two alleles for each gene, one from our mother and one from our father. These different alleles can lead to variations in traits and characteristics.

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Amino Acid

The building blocks of proteins.

Amino acids are the fundamental units that make up proteins. There are 20 different amino acids, each with unique chemical properties. The sequence and arrangement of these amino acids determine a protein's structure and function.

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ApoE4

A variant of ApoE associated with increased risk of Alzheimer's disease.

ApoE4 is a specific form of the ApoE protein linked to a higher likelihood of developing Alzheimer's disease. It plays a role in how fats are transported in the brain and may contribute to the formation of amyloid plaques, a hallmark of the disease.

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ApoE2

A variant of ApoE associated with a slightly reduced risk of Alzheimer's disease.

ApoE2 is another variation of the ApoE protein. Studies have shown that individuals with this variant may have a lower risk of developing Alzheimer's disease compared to those with other ApoE variants.

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Hyperproteinemia

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

Hyperproteinemia is a medical condition where there is an abnormally high amount of protein in the bloodstream. It can be caused by various factors, including dehydration or certain diseases affecting the liver or kidneys.