The USC team linked elevated cPLA2 activity to Alzheimer's risk while studying people who carry the APOE4 gene, the strongest known genetic risk factor for the disease. Although many APOE4 carriers never develop Alzheimer's, researchers found that those with higher cPLA2 activity were more likely to experience the disease.

Because cPLA2 also supports healthy brain function, scientists needed to find a way to reduce its harmful activity without completely shutting the enzyme down. Another challenge involved identifying compounds small enough to cross the blood-brain barrier so they could 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."

Screening Billions of Molecules for Alzheimer's Drug Candidates

To search for potential treatments, researchers used large-scale computational screening methods to evaluate billions of possible molecules. The team prioritized 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 down the list of candidates, pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences led efforts to prepare the compounds for testing in animal models and measure how effectively they reached the brain.

One cPLA2 inhibitor emerged as the leading candidate after reducing harmful cPLA2 activation in human brain cells exposed to Alzheimer's-related stress conditions.

Promising Results in Early Brain and Animal Studies

In mouse studies, the compound successfully crossed the blood-brain barrier and influenced neuroinflammatory pathways linked to Alzheimer's disease. The results suggest that selectively inhibiting cPLA2 may represent 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."

In addition to Yassine, Louie, and Katritch, 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 received funding from the National Institute on Aging (U01AG094622, RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, and P30AG066530); the National Institute of General Medical Sciences (R01GM147537); Department of Defense (W81XWH2110740), the Alzheimer's Drug Discovery Foundation (GC-201711-2014197); USC CTSI KL2 (UL1 TR000004); and donations from the Vranos and Tiny Foundations and Lynne Nauss.

Disclosure: Yassine, Katritch, and Louie are founders of PeBRx, a company developing cPLA2 inhibitors. No other authors reported competing interests.