INDIANAPOLIS — A research team led by Indiana University School of Medicine scientists has discovered a new method for reducing the formation of amyloid plaques, which disrupt brain function in all aging adults but are particularly present in patients with Alzheimer’s disease and related dementias.
The breakthrough, described in a study published in Advanced Science, revolves around the team’s development of molecular glue degrader compounds, which bind the interface of amyloid precursor protein and its regulative protein together in human neurons. These compounds can direct amyloid precursor proteins into the cell’s natural disposal areas, the lysosomes, thus eliminating the proteins. By targeting the proteins that eventually form plaques, the glue degraders could be used therapeutically to reduce the plaques’ production. A U.S. patent “Compounds and methods to treat Alzheimer’s disease” has been filed and published by IU.
“Most current approaches to possible amyloid treatment target the plaques after they have been produced, whereas our approach seeks to intervene earlier by selectively reducing amyloid precursor proteins,” said Chunhai Hao, MD, PhD, Bicentennial Professor of Pathology & Laboratory Medicine II and a corresponding author of the study. “In our Alzheimer’s disease mouse model, treatment with the lead compound reduced amyloid precursor protein and amyloid peptide levels and significantly decreased amyloid plaque burden in the brains.” Hao added the team did not observe any physical or behavioral abnormalities in the mice at the doses tested.
“Additional work will be needed to improve the pharmacology and efficacy of compounds before a compound can enter clinical testing,” Hao said. “If those studies are successful, the longer-term goal would be to advance a lead compound toward clinical trials in people with Alzheimer’s disease.”
Anita Bellail, PhD, associate professor of pathology and laboratory medicine and a corresponding author on the study, led the development of the project’s targeted protein degradation methodologies and molecular glue degrader library. Sunghan Jung, PhD, assistant research professor of pathology and laboratory medicine and the study’s first and a corresponding author, developed special neurons from Alzheimer’s patients to test the library and performed experiments to reveal the mechanism of drug action in stem cell models.
In efforts to translate this research to patient care, Hao and Bellail co-founded a university-based startup, Degrome Therapeutics, with the ultimate goal of developing a treatment that could stop Alzheimer’s disease before it begins — or at least slow its progress.
Other IU researchers who contributed to the project: Xu Wang, PhD; Bin Liu, PhD; Raktim Roy, PhD; Nancy Jaiswal, PhD; Ratan K. Rai, PhD; Yuichiro Takagi, PhD; Cen Gao, PhD; Lifan Zeng, PhD; Reagan K. Wohlford; Ryan K. Higgins and Bruce T. Lamb, PhD.
The research was funded by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.
About the Indiana University School of Medicine
The IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability. According to the Blue Ridge Institute for Medical Research, the IU School of Medicine ranks No. 15 in 2025 National Institutes of Health funding among all public medical schools in the country.
Writer: Rory Appleton, rapplet@iu.edu
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