Pushing the limits to find relationship between proteomics and Alzheimer’s

In 2000, George W. Bush was elected president, the St. Louis Rams won Super Bowl XXXIV, “Breathe” by Faith Hill was the top single and Junmin Peng, PhD, embraced a challenge that would guide his career for the next 20 years.

At the time, Peng was a postdoctoral biochemistry fellow at Harvard Medical School in a laboratory studying Alzheimer’s disease. Alzheimer’s is the most common cause of dementia and the sixth leading cause of death in the U.S. Yet, many questions about the disease, including causes, remain. Treatments to prevent or slow disease progression are lacking. Even the diagnosis is challenging.

Peng wanted to study brain tissue of Alzheimer’s patients, specifically proteins, as protein aggregation occurs in patients’ brains. Changes in protein expression in the brain, he reasoned, may offer insights into the cause and progression of Alzheimer’s and other diseases.

To do that, he moved beyond biochemistry and embraced proteomics. Proteomics is the study of the complete set of proteins that are or can be expressed in given cells or tissue at a given time. He completed a second postdoctoral fellowship in mass spectrometry, a technology to measure mass. The results can help to identify proteins and study how or if their expression changes with disease.

Pushing the technology of proteomics

After completing the second fellowship, Peng joined the Emory University faculty and quickly realized that mass spectrometry was not up to the challenge. “It was not fully ready,” he explained. For example, the more than 14,500 proteins expressed in the brain, such as frontal cortex, was beyond the capacity of mass spectrometry analysis.

He tried a different approach. It also fell short. By 2011, with years of continuous development of mass spectrometry, the technology finally started to catch up with Peng’s vision. By then, Peng was director of the St. Jude Center for Proteomics and Metabolomics. He was also a member of the Departments of Structural Biology and Developmental Neurobiology.

“This study illustrates what can happen when the right idea meets the right technology. The research offers the most comprehensive proteome analysis yet and shows its power to advance understanding of the disorder.” — Junmin Peng, PhD

He and his colleagues used mass spectrometry to identify 36 proteins that aggregate in the brains of people with Alzheimer’s disease. The findings appeared in 2013 in the Proceedings of the National Academy of Sciences. “That’s when we knew that if we pushed the technology a little harder, we would be able to analyze the entire proteome,” he said.

Protein expression and Alzheimer’s

That’s what they did. The investigators, many of them Peng’s current or former postdoctoral fellows, compared protein expression in the brain tissue of adults without Alzheimer’s, adults at different stages of the disease and those with another neurodegenerative disorder. The scientists identified changes in 173 proteins working in 17 pathways associated with Alzheimer’s progression. The findings were verified in two independent groups of Alzheimer’s patients. The results appeared in the journal .

The number of proteins and pathways underscore the devastation of Alzheimer’s disease. “The findings show the entire frontal cortex, which we rely on for memory, decision-making and other fundamental processes, has a problem,” Peng said.

The results reflect analysis of high-resolution mass spectrometry and a technique called tandem mass spectrometry of 14,513 proteins in the frontal cortex. Only about 20% of the proteins had previously been strongly linked to Alzheimer’s. By integrating proteomic and next-generation sequencing data, researchers identified a handful of proteins and pathways as research priorities.

“This study illustrates what can happen when the right idea meets the right technology,” Peng said. “The research offers the most comprehensive proteome analysis yet and shows its power to advance understanding of the disorder.”

Clinical implications of proteomics approach

The findings have already provided leads on better ways to diagnose the disease and track progression. The results have also highlighted important similarities and differences in humans with Alzheimer’s disease and a mouse model used to study the disorder.

The technology, including computer software and the high-throughput pipeline developed for this study, is also being used to understand cancer, immune disorders and other diseases.

“This proteomics approach is universally available to study any biological system and thus any disease,” Peng said.