A USC research team has pinpointed potent new compounds that dial down a key driver of brain inflammation tied to Alzheimer’s disease, without shutting it off completely. The work could lay the groundwork for a new class of treatments aimed at people at high genetic risk.
USC scientists have identified a new way to dial down brain inflammation linked to Alzheimer’s disease, pointing to a promising target for future drugs.
In a study published in the Nature journal npj Drug Discovery, a multidisciplinary team at the University of Southern California reports discovering experimental compounds that home in on an enzyme believed to help drive damaging inflammation in the brain, especially in people at high genetic risk for Alzheimer’s.
The enzyme, known as “calcium-dependent phospholipase A2,” or cPLA2, plays a double role. Earlier work from the team tied elevated cPLA2 activity to brain inflammation in people who carry APOE4, the strongest known genetic risk factor for Alzheimer’s disease. At the same time, cPLA2 is essential for normal brain function, which makes it a tricky drug target: any treatment has to quiet its harmful overactivity without shutting it down.
That balancing act has been a major obstacle for the field. Many anti-inflammatory strategies have failed in Alzheimer’s trials, in part because they were too blunt, affecting broad immune pathways or molecules needed for healthy cells.
The USC team set out to do something more precise.
Using large-scale computational screening, the researchers evaluated billions of potential molecules, looking for those predicted to be highly selective for cPLA2, able to cross the blood-brain barrier and active under realistic biological 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.
From that massive digital search, the scientists narrowed the field to a small set of top candidates. Pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences then led the effort to formulate those compounds so they could be given to animals and to measure how much of each actually reached the brain.
One compound stood out. In human brain cells exposed to Alzheimer’s-related stressors, this cPLA2 inhibitor reduced pathological activation of the enzyme. That made it the team’s lead candidate.
“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,” senior author Hussein Yassine, the director of the Center for Personalized Brain Health at the Keck School of Medicine of USC, said in a news release.
The researchers then moved into mouse models. There, the lead inhibitor successfully crossed the blood-brain barrier, a protective lining that often blocks drugs from entering the brain. Once inside, it modulated neuroinflammatory pathways, suggesting that carefully tuning down cPLA2 activity could calm harmful brain inflammation.
“Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems,” Yassine added.
Alzheimer’s disease affects millions of people worldwide and has long been associated with sticky protein plaques and tangles in the brain. In recent years, scientists have increasingly recognized that chronic inflammation is also a central part of the disease process. Microglia and other immune cells in the brain can become overactive, damaging neurons instead of protecting them.
People who carry the APOE4 gene variant are at especially high risk, but not all APOE4 carriers develop Alzheimer’s. The USC team’s earlier work suggested that elevated cPLA2 may help explain why some carriers progress to disease while others do not, making the enzyme an attractive target for prevention or early intervention.
The new study does not yet test whether the compounds can slow memory loss or other symptoms. Instead, it provides a proof of concept that cPLA2 can be targeted in a nuanced way: enough to change inflammatory signaling, but not so much that normal brain functions are harmed.
“Our goal is to find out whether targeting inflammation can alter Alzheimer’s risk — particularly in APOE4 carriers,” added Yassine.
The researchers emphasize that their work is still at an early, preclinical stage. Before any potential therapy can move into human trials, they will need to refine the compounds, test safety and dosing more extensively in animals, and make sure that long-term modulation of cPLA2 does not produce unwanted side effects elsewhere in the body.
“This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease,” Yassine added.
If future studies confirm that carefully targeting cPLA2 can safely reduce harmful brain inflammation, the approach could open a new front in the fight against Alzheimer’s and possibly other neurodegenerative diseases. For people who know they carry APOE4 and worry about their future, this kind of precision strategy offers a hopeful glimpse of what personalized brain health care might one day look like.