Brain inflammation discovery could lead to new Alzheimer’s treatments

A team has developed a selective compound that inhibits an enzyme tied to inflammation in people at genetic risk for Alzheimer’s disease.

The compound preserves normal brain function while crossing the blood-brain barrier, the protective membrane that separates the brain from the bloodstream.

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 the condition.

While many people who have the APOE4 gene do not develop the disease, those with elevated levels of cPLA2 generally do.

The research was led by Hussein Yassine, director of the Center for Personalized Brain Health at the Keck School of Medicine of USC.

Professor Yassine said: “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.”

Using large-scale computational screening, the team evaluated billions of potential molecules, prioritising those predicted to be selective, brain-penetrant and active under biologically relevant conditions.

Once the team identified the top candidates, researchers formulated 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 stressors related to the condition became the prime candidate.

In mouse models, the inhibitor penetrated the blood-brain barrier and modulated neuroinflammatory pathways, which are involved in inflammation in the nervous system.

The study suggests that inhibiting cPLA2 could be a promising therapeutic approach for neurodegenerative diseases.

Professor Yassine said: “Our goal is to find out whether targeting inflammation can alter Alzheimer’s risk, particularly in APOE4 carriers.

“This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease.”