From Clue to Candidate
The protective role of omega-3 fatty acids in brain health led our team to investigate whether more omega-3s would help APOE4 carriers with Alzheimer's disease. The perplexing answer was that increasing intake did not provide benefits. This suggested that there was an underlying mechanism that needed to be addressed.
Subsequent studies showed that APOE4 carriers accumulate more compounds in their bodies that break down omega-3s, compared to those who do not carry the gene. The effect was even more pronounced in APOE4 carriers who had Alzheimer's disease.
From there, we zeroed in on an enzyme called cPLA2, or calcium-dependent phospholipid A2. Lab results suggested that cPLA2 was responsible for omega-3s being broken down for energy rather than being used for normal brain functions such as forming memories. Importantly, inhibiting that enzyme in lab models increased both the amount of omega-3 fatty acids in the brain and enhanced cognitive function.
Working with colleagues at the USC Michelson Center for Convergent Bioscience, our team searched for a molecule likely to be safe and effective in blocking the action of cPLA2. Using computer modeling to screen a database of more than 18 billion compounds, we found BRI-50054 Further laboratory research indicated that this small molecule lowers cPLA2 activity, increases the amount of omega-3 fatty acids in the brain, and inhibits neuroinflammation.
With BRI-50054 as our inaugural lead compound, the USC Center for Personalized Brain Health is establishing a robust enterprise for moving from biochemical clue to new Alzheimer's treatment.