Alzheimer’s disease affects millions of people around the world. To study this condition, researchers must peer inside the distinctive environment of the human brain.
For scientists to get the most accurate picture of the proteins that drive this disease, they must extract them without altering their environment.
In a study published in Protein Science, researchers at the FAMU-FSU College of Engineering demonstrated a new method for studying Alzheimer’s disease that keeps disease-causing proteins intact in a near-native environment, helping scientists get a more accurate picture of how they function.
“Alzheimer’s disease is devastating,” said Professor Ayyalusamy Ramamoorthy, a co-author of the study. “More people are living longer, and that means more people are going to be living with Alzheimer’s disease, so we need to find a cure for it and other aging-related amyloid diseases, like Parkinson’s and Type 2 diabetes. Attempts to develop drugs for Alzheimer’s disease have failed, so we started to work on the C99 protein, which is the origin for everything.”
What they did
Researchers developed a method to extract a key protein involved in the progression of Alzheimer’s disease called C99.
Previously, C99 was difficult to study, as samples had to be removed from cells and prepared for analysis using detergents. The harsh, soap-like chemicals break down lipids, or fats, that surround C99 in the brain and influence how it behaves. Without lipids, C99’s behavior changes, and scientists were unable to study how it acts in its natural environment in the brain.
By using a non-detergent-based polymer to capture C99, the natural environment of the brain cells where the protein is found was preserved, providing researchers with a new way to study it.
“We have been developing these synthetic polymers that can extract proteins present in the cell membrane directly without using detergents,” Ramamoorthy said. “This work was about using synthetically prepared polymers in my lab to isolate a precursor protein along with the lipids present in the cell membrane and reconstituting them together in the form of disc-shaped particles called nanodiscs for a deeper medical investigation.”
How it works
C99 is a byproduct of the amyloid precursor protein, or APP, which is found in the brain.
When enzymes known as secretases cut APP, they produce fragments of C99 called Aβ isomers. The accumulation of Aβ and lipids causes plaque buildup, which is responsible for memory loss in Alzheimer’s patients by killing neuronal cells.
In this study, researchers isolated the C99 protein from a bacterial cell membrane then extracted it along with lipids surrounding C99 using their newly designed polymer. After extraction, researchers conducted further tests to confirm that the protein’s shape and lipids were still intact and preserved exactly as they are in cells.
Why it matters
This study represents a revolutionary advancement in Alzheimer’s research by keeping a key disease-causing protein intact for more accurate study.
“This work provides a toolkit for studying Alzheimer’s disease at the molecular level and it lets scientists observe C99 in its ‘natural habitat,’ which is something that had not been possible in more than 30 years of research,” Ramamoorthy said. “It creates a biomedically relevant and more accurate method for preparing proteins used in therapeutic discovery and Alzheimer’s disease modeling.”
The research could improve outcomes for pharmaceutical development, medical diagnostic and imaging tools or biotechnology manufacturing. The new method provides a foundation for further research that could one day lead to a cure.
“Drug development has so far not been able to solve the problems posed by Alzheimer’s disease,” Ramamoorthy said. “Our hope is that this new method will give researchers a clearer picture of how the C99 protein works and contributes to this disease, so that we can develop ways to stop its progression. Ultimately, we can find a cure.”
Researchers from the University of Michigan contributed to this study. This research was supported by the National Institutes of Health.
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