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by Hannah Buckelew
More than six million Americans are living with Alzheimer’s disease (AD), the leading cause of dementia worldwide, and nearly 95 percent of all AD cases are late-onset. However, the current success rate for AD drug development is very low. Yuhua Song, Ph.D., a professor in the Department of Biomedical Engineering, has been awarded an R01 grant from the National Institutes of Health’s National Institute on Aging funding her research on drug repositioning to target TREM2 in AD. The grant is funded at $2.89 million over five years, through 2028.

AD is greatly affected by genetic factors. TREM2 is a protein found on the surface of myeloid cells, or cells produced in bone marrow, and plays an important role in regulating inflammatory responses in immune cells. Single amino acid variants in TREM2 have been identified by studies to be one of the strongest genetic risk factors for late-onset AD and AD-associated variants affecting immunity.

“New knowledge gained from this study could have a major impact for AD research and treatment,” Song says. “By repositioning available drugs, we can search for new drug combinations to target TREM2 for AD treatment.”

In previous studies, Song’s team identified two ligand binding sites in TREM2, including a basic site that contains most of the AD-associated residues on TREM2, and a hydrophobic site located near complementarity-determining regions of antibodies. Song’s team believes that available drugs, including FDA-approved drugs, could bind TREM2 at one of these two binding sites to regulate ligand and modulate TREM2-mediated immune activation in AD.

To test this hypothesis, Song’s team specifically aims to identify available drugs bound at basic and/or hydrophobic binding sites on TREM2 with unbiased virtual screening and biophysical and biological experimental validation. The team will then characterize the interactions of available drugs with TREM2 to determine the allosteric effect of available drug binding at basic and hydrophobic TREM2 binding sites, and on TREM2-mediated immune activation. Finally, the team aims to determine whether the available drugs could counteract the loss of its immune activities caused by AD-associated TREM2 variants.

“We think that available drugs bound at TREM2 basic or hydrophobic sites can regulate each other to modulate immune activation,” Song says.

Song’s UAB collaborators on this R01 grant include Erik Roberson, M.D., Ph.D., in the Department of Neurology. External collaborators include Thomas Brett, Ph.D., and Arthur Romero, Ph.D., at Washington University in St. Louis and Li Gan, Ph.D., at Weill Cornell Medicine. Song wants to acknowledge the contributions of her lab members, particularly graduate students Rory Greer and Hunter Dean.