Alzheimer’s disease (AD) involves the buildup of harmful proteins in the brain. Hereditary changes in the brain resident immune cells, called microglia can strongly affect this process. One of the factors that affect the microglia responses to disease, is “Paired immunoglobulin-like type 2 receptor alpha” or PILRA. PILRA normally acts like a brake that slows down microglia. A rare, natural change in the PILRA gene that blocks its activity has been linked to lower risk of Alzheimer’s disease, but scientists did not fully understand its mechanism.
In this study, co-led by researchers from Denali therapeutics and Blurton-Jones Lab at UCI, human stem cell–derived microglia and mouse models of Alzheimer’s disease were leveraged to investigate what happens when PILRA is removed or blocked. These researchers found that getting rid of PILRA allows microglia to work more efficiently through boosting their energy production, fat processing and storage capacities, and enhanced immune responses to disease. In mice with Alzheimer-like brain changes, microglia lacking PILRA helped clear amyloid buildup and protected connections between brain cells. The team also tested an antibody that blocks PILRA and found it produced similar benefits. These results reveal how reducing PILRA activity can make microglia more protective and may lower Alzheimer’s-related brain damages. Overall, the study identifies PILRA as a promising new target for future Alzheimer’s treatments. This work was published in the journal of Science Translational Medicine and was selected as the cover for the issue.
