Selective inhibition of cPLA2 shows promise against Alzheimer's-related brain inflammation

A multidisciplinary USC research team has identified new compounds that may target a key driver of brain inflammation linked to Alzheimer's disease. Their research just published in the Nature publication npj Drug Discovery.

The driver is an enzyme called "calcium-dependent phospholipase A2," or 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. Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems."

Hussein Yassine, senior author, director of the Center for Personalized Brain Health, Keck School of Medicine of USC

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."

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 authors include Brandon Ebright, Dante Dikeman, Cristelle Hugo, Bilal Ersen Kerman, Qiu-Lan Ma, Antonina L. Nazarova, Arman A. Sadybekov and Isaac Asante, all of USC.

The research was supported with grants 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.