The project led by Dr. Therrien is assessing how various genetic risk factors for Alzheimer’s disease impact the human microglial response to peripheral inflammation. While recent research highlights how several known risk factors expressed by microglia (e.g., TREM2, CD33, APOE) contribute to Alzheimer’s pathology, the focus thus far has been on how single gene variants act alone to change a cell’s response to perturbations in the brain. Dr. Therrien is interested in exploring how multiple risk genes work together to activate microglia after peripheral inflammation. Scientists and doctors rely on a Polygenic Risk Score (PRS) to quantify the cumulative effects of multiple gene variants on disease risk. However, experimentally testing the impact of combinations of risk variants on microglial function is complex and difficult. Dr. Therrien has established several novel technical approaches to make this feasible. The Therrien team hypothesizes that genetic variants that increase the risk for Alzheimer’s disease impact the microglial response to LPS injection and signaling through the TLR4 protein.
The Therrien lab plans to transplant human microglia cells into mice. However, these microglia come from human donors with either high or low PRS and across different APOE variants (E2, E3, E4). Using a clever experimental design, the team pools microglia into microglia villages, transplants them into the same mouse, and later disentangles the relationship between PRS, APOE, and microglial activation following peripheral inflammation. They are pursuing three aims. First, they are exploring how PRS identifies specific risk genes that modify microglial activation over time following LPS injection. Second, they are examining the role of TLR4 in mediating the PRS effects on microglia activation following peripheral inflammation and in the presence of amyloid beta. Third, they are testing how gene variants and TNF-α, another potential intermediary cytokine signal that increases following LPS injection, affect microglial activation in the brain.
In their first year of funding, the Therrien lab has achieved impressive progress across all three aims. Dr. Therrien successfully established their lab at UC Davis and implemented models using human-derived microglia transplanted into mice. For the first aim, they found that the TLR4 and TNF pathways consistently activate an inflammation response, regardless of AD genetic risk level. This suggests that genetic risk factors may require interaction with other variables to influence disease progression. The team is now analyzing additional time points and gene expression profiles across microglial populations to identify subtle differences between high- and low-risk AD profiles. Progress toward aim two is underway, with the team actively designing probes to knock down TLR4 expression and explore its role in microglial activation. For aim three, they are developing in vitro triculture models to study how interactions between various brain cell types shape inflammatory responses. In the coming year, they plan to expand these studies.
