Understanding the Link Between Alzheimer's Disease Risk Genes and Immune Responses in the Brain

This project will help us understand the mechanisms behind how genetic risk for AD alters immune activation and test whether or not altering immune activation can halt disease progression.

Large scale studies of genetic risk factors for Alzheimer’s disease (AD) have revealed that AD-risk genes are highly expressed in immune cells. This suggests that changes in immune function have potential to alter someone’s risk of disease onset, representing a novel therapeutic target. To uncover common mechanisms that underlie AD risk, I will perform a high throughput screen of immune cell function after perturbing AD-risk genes. I will also test the impact of these immune activation states in mouse models to determine how blocking or enriching immune activation states alters AD progression.

My proposal leverages high-throughput CRISPR screening as a discovery platform to nominate AD-risk genes that directly impact microglial activation at the transcriptomic level and in a synaptic pruning assay. These unbiased experiments will deepen our understanding of the AD-risk landscape and uncover convergent pathways between risk genes.
I propose to translate these findings into a chimeric mouse model of Alzheimer’s disease that allows for engraftment of human iPSC-derived microglia into the murine brain environment. Here, I will study microglia that have been pre-directed into or out of specific activation states to understand the impact of these immune activation states on brain healt

By understanding how microglial states and function are altered in response to AD-risk variants, we will be better poised to develop therapies directing microglia towards disease-protective states. When this study is complete, we will have directly tested the impact of two such states on brain health and provide proof-of-concept data towards development of microglia cell therapies targeting these activation states.