Researchers at the University of Southern California have identified an experimental compound that may help reduce brain inflammation associated with Alzheimer’s disease. The research results were published in the journal Nature npj drug discoveryfocuses on an enzyme called calcium-dependent phospholipase A2 (cPLA2), which appears to play an important role in inflammation in the brain.
The USC team linked elevated cPLA2 activity to Alzheimer’s risk while studying people with the APOE4 gene, the strongest known genetic risk factor for Alzheimer’s disease. Researchers found that while many APOE4 carriers do not develop Alzheimer’s disease, those with high cPLA2 activity are more likely to experience Alzheimer’s disease.
Because cPLA2 also supports healthy brain function, scientists needed to find a way to reduce its harmful activity without completely blocking the enzyme. Another challenge involved identifying compounds small enough to cross the blood-brain barrier and effectively reach the brain.
“In this study, we identified a compound that selectively acts on cPLA2 while minimizing effects on the associated PLA2 enzyme, which is important for normal cell function,” said senior author Hussein Yassin, 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 this compound is potent in brain-related systems.”
Screening billions of molecules for Alzheimer’s disease drug candidates
To search for potential treatments, researchers used large-scale computational screening methods to evaluate billions of possible molecules. The research team prioritized compounds that were predicted to selectively target cPLA2, enter the brain, and remain active under biologically relevant conditions. This screening method was developed by Vsevolod “Seva” Katrich of the USC Dornsife College of Letters, Arts and Sciences and the USC Michaelson Center for Convergent Bioscience.
After narrowing down the list of candidates, Stan Lui, a pharmacologist at the University of Southern California’s Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, led an effort to prepare compounds for testing in animal models and measure how effectively they reach the brain.
A cPLA2 inhibitor has emerged as a potential candidate after reducing harmful cPLA2 activation in human brain cells exposed to Alzheimer’s disease-related stress conditions.
Promising results in early brain and animal studies
In mouse studies, this compound successfully crossed the blood-brain barrier and affected neuroinflammatory pathways associated with Alzheimer’s disease. This result suggests that selectively inhibiting cPLA2 may be a promising strategy for the treatment of neurodegenerative diseases.
“Our goal is to find out whether targeting inflammation can alter the risk of Alzheimer’s disease, especially in APOE4 carriers,” Yassin said. “This next step is focused on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease, rather than promises.”
In addition to Yassine, Louie, and Katrich, the study was led by co-first authors Anastasiia V. Sadybekov, Marlon Vincent Duro, and Shaowei Wang (all of USC). Other contributors include Brandon Ebright, Dante Dijkman, Christel Hugo, Bilal Elsen Kelman, Qiu-Lan Ma, Antonina L. Nazarova, Arman A. Sadibekov, and Isaac Asante.
This research was funded by the National Institute on Aging (U01AG094622, RF1AG076124, R01AG055770, R01AG067063, R01AG054434, R21AG056518, and P30AG066530). National Institute of General Medical Sciences (R01GM147537); Department of Defense (W81XWH2110740); Alzheimer’s Disease Drug Discovery Foundation (GC-201711-2014197). USC CTSI KL2 (UL1 TR000004); contributions from Vranos and Tiny Foundations and Lynne Nauss.
Disclosure: Yassin, Katrich, and Lui are founders of PeBRx, a company developing cPLA2 inhibitors. No other authors reported any competing interests.
