Researchers discover insights into amyloids associated with Alzheimer's and type 2 diabetes

June 26, 2018 by Kristin Rose, Virginia Tech
Using the Virginia Tech HyperCube immersive environment, Justin Lemkul (left) and Anne Brown (right) examine the structure of amyloid β-peptide associated with Alzheimer’s disease.

A Virginia Tech research team has discovered insights into the stabilizing forces of amyloid fibrils that are associated with Alzheimer's disease and type 2 diabetes.

These findings were recently published in the Journal of Molecular Biology.

Amyloids are aggregates of proteins that form a shape that allows many copies of that to stick together to form fibrils. The accumulation of amyloid fibrils in the brain contributes to Alzheimer's disease, and the accumulation of amyloid fibrils in the pancreas contributes to type 2 diabetes by damaging cells that produce insulin.

Justin Lemkul, an assistant professor of biochemistry in the College of Agriculture and Life Sciences, and his team's research focuses on applying computer simulations to understand mechanisms of protein aggregation that are difficult or even impossible to recreate in a laboratory setting.

Elucidating the structure and stability of these amyloid fibrils is important for developing future anti-amyloid drug therapies.

For this research, Lemkul's team performed the first-ever simulations of amyloid fibrils using a physical model that included electronic polarization to understand the forces stabilizing three amyloid-forming proteins observed in Alzheimer patients: microtubule-associated protein tau, amyloid β-peptide, and islet amyloid polypeptide (IAPP). IAPP is also associated with amyloid fibrils in type 2 diabetes patients.

"We found that several amino acids in these three amyloid-forming proteins are particularly sensitive to small changes in their environment, particularly glycine, which plays a major role in stabilizing amyloid aggregates," said Lemkul, an affiliate of the Fralin Life Science Institute and Virginia Tech Center for Drug Discovery.

Anne Brown, an assistant professor in research and informatics, University Libraries, is a contributing author and performed the IAPP simulations and analysis for the paper.

Structures of amyloid fibrils used in the study colored in rainbows to show directionality of amino acids. (a) and (b) microtubule-associated protein tau associated with Alzheimer’s disease (c) amyloid β-peptide associated with Alzheimer’s disease (d) and (e) islet amyloid polypeptide (IAPP) associated with Alzheimer’s disease and type 2 diabetes. Courtesy of Justin Lemkul
"The sequences of these three amyloids fibrils vary greatly in composition and length, but all participate in an aggregation pathway that results in these fibril structures. It is common to study individually; however, by studying three very different amyloid fibrils together, we were able to determine stabilizing forces that were common among them. This gives us new directions for understanding amyloids in general and a better understanding of how some amyloids result in disease states," said Brown.

With these new insights, researchers can begin to design drugs to break up the amyloid fibrils or prevent them from forming in the first place.

"Therapeutic intervention will be most helpful if researchers can design drugs that prevent the fibril formation," said Lemkul.

Darcy Davidson, the first author on the paper and a first-year graduate student in Lemkul's lab, began her research on microtubule-associated tau as part of her rotation project.

"Both of my grandfathers were diagnosed with Alzheimer's, so this research is personal and important to me. These discoveries can help researchers develop better drugs to target specific areas of amyloid fibril formation, and this is exciting in terms of future treatment for Alzheimer's," said Davidson.

Davidson is currently continuing her research on microtubule-associated protein tau focusing on protein folding and how single proteins begin to aggregate to form an fibril.

Lemkul's team is interested in future collaboration with researchers to test these discoveries in the laboratory and in animal models; researchers can then begin to design drugs to target and prevent the formation of .

Amyloid formation is associated with a variety of human diseases, including Alzheimer's disease (AD), type 2 diabetes (T2D), Parkinson's, rheumatoid arthritis, Huntington's disease, and more.

Explore further: 'Antifreeze' molecules may stop and reverse damage from brain injuries

More information: Darcy S. Davidson et al. Insights into Stabilizing Forces in Amyloid Fibrils of Differing Sizes from Polarizable Molecular Dynamics Simulations, Journal of Molecular Biology (2018). DOI: 10.1016/j.jmb.2018.05.020

Related Stories

'Antifreeze' molecules may stop and reverse damage from brain injuries

June 21, 2018
The key to better treatments for brain injuries and disease may lie in the molecules charged with preventing the clumping of specific proteins associated with cognitive decline and other neurological problems, researchers ...

Amyloid formation may link Alzheimer disease and type 2 diabetes

February 17, 2015
The pathological process amyloidosis, in which misfolded proteins (amyloids) form insoluble fibril deposits, occurs in many diseases, including Alzheimer disease (AD) and type 2 diabetes mellitus (T2D). However, little is ...

A stronger twist to cytotoxic amyloid fibrils

October 24, 2017
Researchers from Amsterdam and Enschede have for the first time performed a structural comparison of two types of amyloid fibrils that have been associated with Parkinson's disease. Using a combination of experimental methods ...

Recommended for you

Gene plays critical role in noise-induced deafness

October 19, 2018
In experiments using mice, a team of UC San Francisco researchers has discovered a gene that plays an essential role in noise-induced deafness. Remarkably, by administering an experimental chemical—identified in a separate ...

Functional engineered oesophagus could pave way for clinical trials 

October 18, 2018
The world's first functional oesophagus engineered from stem cells has been grown and successfully transplanted into mice, as part of a pioneering new study led by UCL.

New findings cast light on lymphatic system, key player in human health

October 16, 2018
Scientists at the Oklahoma Medical Research Foundation have broken new ground in understanding how the lymphatic system works, potentially opening the door for future therapies.

New model suggests cuffless, non-invasive blood pressure monitoring possible using pulse waves

October 16, 2018
A large team of researchers from several institutions in China and the U.S. has developed a model that suggests it should be possible to create a cuffless, non-invasive blood pressure monitor based on measuring pulse waves. ...

Age-related increase in estrogen may cause common men's hernia

October 16, 2018
An age-related increase in estrogen may be the culprit behind inguinal hernias, a condition common among elderly men that often requires corrective surgery, according to a Northwestern Medicine study was published Oct. 15 ...

Income and wealth affect the mental health of Australians, study shows

October 16, 2018
Australians who have higher incomes and greater wealth are more likely to experience better mental health throughout their lives, new research led by the Bankwest Curtin Economics Centre has found.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.