New Target Identified for Alzheimer's Brain Inflammation

A multidisciplinary team has developed a selective compound that inhibits an enzyme tied to inflammation in people at genetic risk for Alzheimer's, while preserving normal brain function and crossing the blood-brain barrier. The findings are published in the journal npj Drug Discovery. The driver is an enzyme called calcium-dependent phospholipase A2 (cPLA2). The team discovered its role in brain inflammation by studying people who carry the APOE4 gene—the strongest genetic risk factor for Alzheimer's disease. While many people who have the APOE4 gene don't develop the disease, those with elevated levels of cPLA2 generally do. The problem is that cPLA2 is also essential for normal brain function, so any potential drug molecule would need to inhibit the enzyme's activity without eliminating it. The molecular candidate would also need to be small enough to cross the blood brain barrier to be effective. "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." Alzheimer's-linked brain inflammation: Evaluating molecules Using large-scale computational screening, the team evaluated billions of potential molecules, prioritizing those predicted to be selective, brain-penetrant and active under biologically relevant conditions. Vsevolod "Seva" Katritch of the USC Dornsife College of Letters, Arts and Sciences and the USC Michelson Center for Convergent Bioscience developed the screening methods. Once the team identified the top candidates, pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences led the effort to formulate those compounds for administration in animal models and test their levels in the brain. A cPLA2 inhibitor that reduced pathological cPLA2 activation in human brain cells exposed to Alzheimer's-related stressors became the prime candidate. In mouse models, the inhibitor penetrated the blood-brain barrier and modulated neuroinflammatory pathways. The study suggests that inhibiting cPLA2 could be a promising therapeutic approach for neurodegenerative diseases. "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."