Researchers believe an imbalance of peptides leads to Alzhiemer’s progression. Photo Credit: Rensselaer Polytechnic Institute/Caitlin Piette

Chunyu Wang, assistant professor of biology, is challenging current thinking on the causes and prevention of Alzheimer’s disease, offering a new hypothesis that could be the key to preventing this form of dementia. He has found that a specific imbalance between two peptides may be the cause of the fatal neurological disease that affects more than five million people in the United States.

“We have found that two peptides, Aβ42 and Aβ40, must be in balance for normal function,” said Wang. “They are like the Yin and Yang in Taiji, an ancient Chinese philosophy. When the peptides are produced in the correct proportions, the brain is healthy; but when that delicate balance is changed, pathological changes will occur in the brain and the person’s memories become hazy, leading to eventual dementia.”

Wang expects that this imbalance could be the main factor in the progression of Alzheimer’s disease. If correct, the addition of Aβ40 may stop the disease’s development. Wang notes that further research is needed, but his preliminary results challenge the current mode of thinking about how these peptides contribute to the progression of the disease. 

The research will be published in the June edition of the Journal of Molecular Biology.

Peptides are formed by the linking of different amino acids. The two peptides that Wang investigated were both Amyloid β-peptides (Aβ) — specifically those composed of 40 and 42 amino acids, called Aβ40 and Aβ42. These two peptides have been previously found in deposits, called senile plaques or amyloid plaques, in brains afflicted with Alzheimer’s disease. These plaques, mainly composed of Aβ42 fibrils, are a hallmark of Alzheimer’s disease.

Prior research has uncovered that increased levels of Aβ42 become toxic to brain cells when individual molecules of Aβ42, or monomers, combine to form oligomer or fibril chains. This process is called aggregation. But the role of Aβ40, which is also found in senile plaques and generated from the same protein as Aβ42, has not been clearly established. Wang set out to determine what role this peptide played in the generation of Aβ42 aggregates.

Wang used the advanced Nuclear Magnetic Resonance (NMR) machines within the Center for Biotechnology and Interdisciplinary Studies to monitor the formation of harmful Aβ42 fibrils in the presence of different levels of Aβ40. 

As levels of Aβ40 decrease, levels of harmless Aβ42 monomers also decrease as the monomers form harmful oligomers. Photo Credit: Rensselaer Polytechnic Institute/Yilin Yan

Using NMR data, Wang found that as Aβ40 levels increased, the aggregation of Aβ42 fibrils sharply decreased, protecting benign Aβ42 monomers.  

Wang’s experiments show that when there is 15 times more Aβ40 than Aβ42, the formation of Aβ42 fibrils is almost completely stopped. “This means that the introduction of Aβ40 to tip the peptide balance toward Aβ40 could potentially halt or slow down the progression of the Alzheimer’s in the human brain,” Wang said.

Wang plans to continue investigating how Aβ40 halts the formation of Aβ42 fibrils, and he already sees vast implications for this change in thinking about the progression of the disease.

“This has the potential to become a simple therapy to prevent the formation of toxic Aβ42 species,” he said. “I plan to continue my research on the role of Aβ40 and hope that we can test this theory on human neurons, animal models, and someday in clinical trials.” 

The research was funded by the Alzheimer’s Association and a New York State Office of Science, Technology, and Academic Research (NYSTAR) James D. Watson Investigator Program Award.

Rensselaer graduate student Yilin Yan worked with Wang on the research project.

Published June 4, 2007