Yin and Yang: Balance Could Play Key Role in Progression of Alzheimer’s Disease

Newswise — Researchers at Rensselaer Polytechnic Institute are 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. The researchers have 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 Chunyu Wang, lead researcher and assistant professor of biology at Rensselaer. "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 Rensselaer's Center for Biotechnology and Interdisciplinary Studies to monitor the formation of harmful Aβ42 fibrils in the presence of different levels of Aβ40. NMR is an extremely powerful research tool capable of characterizing the three-dimensional structure and dynamics of biological molecules.

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

"We have found that the ratio of Aβ40 to Aβ42 plays a key role in Aβ42 aggregation," Wang said. "The current mode of thinking in Alzheimer's emphasizes the toxic role of Aβ42 but neglects the protective role of Aβ40. Combined with previous work on Aβ40 by many other groups, our data suggest that Aβ40 has an equally important, protective role in Alzheimer's. Thus Aβ42, the bad molecule, and Aβ40, the good molecule, are like Yin and Yang in Taiji. The brain can only function normally when they are in balance."

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. One critical advantage of using Aβ40 for the prevention or therapy for Alzheimer's is that Aβ40 is already known to be largely free of side effects at near physiological concentration."

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.

About Rensselaer Rensselaer Polytechnic Institute, founded in 1824, is the nation's oldest technological university. The university offers bachelor's, master's, and doctoral degrees in engineering, the sciences, information technology, architecture, management, and the humanities and social sciences. Institute programs serve undergraduates, graduate students, and working professionals around the world. Rensselaer faculty are known for pre-eminence in research conducted in a wide range of fields, with particular emphasis in biotechnology, nanotechnology, information technology, and the media arts and technology. The Institute is well known for its success in the transfer of technology from the laboratory to the marketplace so that new discoveries and inventions benefit human life, protect the environment, and strengthen economic development.