Molecular glue degraders show early promise in reducing Alzheimer's-linked brain plaques
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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 prevalent in patients with Alzheimer's disease and related dementias.
The advance, described in a study published in Advanced Science, revolves around the team's development of molecular glue degrader compounds, which bind amyloid precursor protein and its regulatory protein together at their interface 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.
Targeting precursors before plaques form
"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, M.D., Ph.D., bicentennial professor of pathology and 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 brain." Hao added that 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."
From patient-derived neurons to potential treatment
Anita Bellail, Ph.D., 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, Ph.D., assistant research professor of pathology and laboratory medicine and the study's first author 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.
Publication details
Sunghan Jung et al., Molecular Glue Degraders Enhance CAPRIN1‐Dependent Lysosomal Degradation of APP and Reduce Amyloid β in Alzheimer's Disease, Advanced Science (2026). DOI: 10.1002/advs.77575
Journal information: Advanced Science
Key medical concepts
Amyloid beta-Protein PrecursorAlzheimer's DiseaseNeuritic Plaque
Clinical categories
NeurologyClinical pharmacology Provided by Indiana University Who's behind this story?
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