A groundbreaking study by a multidisciplinary research team at the University of Southern California (USC) has identified novel compounds that target a critical enzyme linked to brain inflammation in Alzheimer’s disease. The findings, recently published in the journal npj Drug Discovery, highlight the potential of these compounds to mitigate neuroinflammatory processes associated with Alzheimer’s.
The enzyme in question, known as “calcium-dependent phospholipase A2” or cPLA2, plays a significant role in brain inflammation. Researchers focused on individuals carrying the APOE4 gene, the strongest genetic risk factor for Alzheimer’s. Although not all APOE4 carriers develop the disease, elevated cPLA2 levels are commonly observed in those who do.
Innovative Approach to Inhibiting cPLA2
The challenge for researchers was to develop a compound that could selectively inhibit cPLA2 without disrupting its essential functions in normal brain activities. Additionally, any potential treatment must be able to cross the blood-brain barrier to be effective.
According to Dr. Hussein Yassine, the study’s senior author and director of the Center for Personalized Brain Health at the Keck School of Medicine of USC, “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. Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems.”
Alzheimer’s-Linked Brain Inflammation: Evaluating Molecules
Utilizing large-scale computational screening, the research team evaluated billions of potential molecules, prioritizing those predicted to be selective, brain-penetrant, and active under biologically relevant conditions. This innovative screening method was developed by Vsevolod “Seva” Katritch of the USC Dornsife College of Letters, Arts and Sciences and the USC Michelson Center for Convergent Bioscience.
Once the top candidates were identified, pharmacologist Stan Louie from the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences spearheaded the formulation of these compounds for animal model testing. A promising cPLA2 inhibitor demonstrated reduced pathological activation in human brain cells exposed to Alzheimer’s-related stressors.
Animal Model Success
In mouse models, the inhibitor successfully penetrated the blood-brain barrier and modulated neuroinflammatory pathways. This suggests that targeting cPLA2 could be a viable therapeutic strategy for neurodegenerative diseases.
“Our goal is to find out whether targeting inflammation can alter Alzheimer’s risk—particularly in APOE4 carriers,” Yassine stated. “This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease.”
Collaborative Effort and Future Directions
The study was a collaborative effort involving co-first authors Anastasiia V. Sadybekov, Marlon Vincent Duro, and Shaowei Wang, among others from USC. The research was supported by grants from the National Institute on Aging, the National Institute of General Medical Sciences, the Department of Defense, and the Alzheimer’s Drug Discovery Foundation, alongside donations from the Vranos and Tiny Foundations and Lynne Nauss.
The next steps involve further testing to ensure safety and efficacy in humans, with the hope of developing a new class of drugs to combat Alzheimer’s disease. This research represents a significant step forward in understanding and potentially mitigating the inflammatory processes that contribute to Alzheimer’s and other neurodegenerative conditions.
