Chunyu Wang, M.D., Ph.D., professor of biological sciences and chemistry and chemical biology at Rensselaer Polytechnic Institute, has been awarded a five-year grant of more than $3.7 million by the National Institutes of Health’s National Institute on Aging to study Apolipoprotein E (ApoE) isoform interactions with heparan sulfate (HS) in Alzheimer’s disease (AD). 

“At first, my research was motivated by my curiosity of how the brain and memory work,” said Wang. “However, over the years, I have known many people affected by Alzheimer’s disease, so I am more and more motivated by the urgent need for discovering more effective, safer, and affordable drugs for Alzheimer’s disease.” 

According to the Alzheimer’s Association, one in nine people aged 65 and older has Alzheimer’s. That’s 6.9 million Americans living with the disease, and millions more who are caring for them. What is already a startling number is projected to grow as our aging population does, and by 2050, 12.7 million Americans aged 65 and older will have Alzheimer’s.

“With this funding, we will explore how ApoE isoforms modulate the risk of Alzheimer’s disease through their distinct interactions with heparan sulfate,” said Wang. “Ultimately, we hope to discover new therapy strategies for Alzheimer’s disease.”

ApoE is a protein that combines with lipid molecules to shuttle cholesterol throughout the body, including from astrocytes to neurons in the brain. One of the ApoE genotypes, ApoE4, is the biggest genetic risk factor for late onset Alzheimer’s disease (LOAD). In contrast, ApoE2, another genotype, protects against LOAD; while the most common genotype, ApoE3, is considered to be neutral for AD risk. ApoE2 and ApoE4 only differ from ApoE3 by a single amino acid. 

The mechanisms of how these single amino acid changes can modulate AD risk are extremely important but poorly understood. Heparan sulfate is a sugar molecule present on neuronal surfaces. Wang’s group has previously shown that how strongly HS binds ApoE correlates with AD. For example, ApoE4 binds HS stronger, with higher AD risk; while ApoE2 binds HS weaker, with lower AD risk. With this grant, Wang will define these different interactions of ApoE isoforms and, ultimately, study them in cellular and animal models. These data will provide new insights for AD drug discovery. 

“Professor Wang has already contributed so much to our understanding of the mechanisms of Alzheimer’s disease,” said Curt Breneman, Ph.D., dean of Rensselaer’s School of Science. “His new work adds the exciting potential for discovering new drug targets that could lead to therapies to slow its progress, inspiring hope for so many individuals and families who are affected by this terrible degenerative disease.”

Wang has about 20 years of experience applying nuclear magnetic resonance (NMR) spectroscopy to study the structural biology of proteins involved in neurodegenerative diseases and cancer. He has published over 110 scientific articles and has presented his work at over 80 venues. Wang is affiliated with the Center for Engineering and Precision Medicine (CEPM), which was launched in New York City last year by Rensselaer and the Icahn School of Medicine. Wang is also a member of Rensselaer’s Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies. 

“Thanks to this grant, Professor Wang’s research will bring exciting possibilities for Alzheimer’s disease treatments,” said Deepak Vashishth, co-director of CEPM. “It is a critical area of research with our aging population.”