A USC research team says it has identified experimental compounds that may cut brain inflammation linked to Alzheimer’s disease, with a focus on people who carry the high-risk APOE4 gene.
The findings, published in npj Drug Discovery, centre on an enzyme called calcium-dependent phospholipase A2, or cPLA2, which the researchers say appears to play an important role in inflammation inside the brain.
The team linked elevated cPLA2 activity to Alzheimer’s risk while studying people who carry APOE4, the strongest known genetic risk factor for the disease. The researchers found that APOE4 carriers with higher cPLA2 activity were more likely to experience Alzheimer’s disease, although many APOE4 carriers never develop it.
Because cPLA2 also supports healthy brain function, the researchers said they needed to reduce its harmful activity without completely shutting the enzyme down. They also needed compounds small enough to cross the blood-brain barrier and reach the brain effectively.
“In this study, we identified compounds that act selectively on cPLA2, with minimal effects on related PLA2 enzymes that are important for normal cellular function,” said senior author Hussein Yassine, director of the Center for Personalized Brain Health at the Keck School of Medicine of USC.
“Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems.”
To search for possible treatments, the researchers used large-scale computational screening methods to evaluate billions of molecules. The team prioritised compounds predicted to selectively target cPLA2, enter the brain, and remain active under biologically relevant conditions.
The screening methods were developed by Vsevolod “Seva” Katritch of the USC Dornsife College of Letters, Arts and Sciences and the USC Michelson Center for Convergent Bioscience.
After narrowing the list, pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences led work to prepare the compounds for testing in animal models and to measure how effectively they reached the brain.
One cPLA2 inhibitor became the leading candidate after it reduced harmful cPLA2 activation in human brain cells exposed to Alzheimer’s-related stress conditions.
In mouse studies, the compound crossed the blood-brain barrier and influenced neuroinflammatory pathways linked to Alzheimer’s disease. The researchers said the results suggest selectively inhibiting cPLA2 may be a promising strategy for treating neurodegenerative disorders.
“Our goal is to find out whether targeting inflammation can alter Alzheimer’s risk, particularly in APOE4 carriers,” Yassine said.
“This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease.”
The study was led by co-first authors Anastasiia V. Sadybekov, Marlon Vincent Duro, and Shaowei Wang, all of USC. Other contributors included Brandon Ebright, Dante Dikeman, Cristelle Hugo, Bilal Ersen Kerman, Qiu-Lan Ma, Antonina L. Nazarova, Arman A. Sadybekov, and Isaac Asante.
The research was funded by the National Institute on Aging, the National Institute of General Medical Sciences, the Department of Defense, the Alzheimer’s Drug Discovery Foundation, USC CTSI KL2, and donations from the Vranos and Tiny Foundations and Lynne Nauss. Yassine, Katritch, and Louie are founders of PeBRx, a company developing cPLA2 inhibitors.
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