Microglia, the resident immune cells of the brain, have been implicated in Alzheimer’s disease (AD) for years. Normally, microglia protect the brain by clearing toxic proteins like amyloid beta. However, in AD, microglia either lose this vital cleanup function or become chronically overactivated, which worsens inflammation and contributes to brain cell damage.
When microglia encounter damage in the AD brain, they shift into a disease-associated state (often called the DAM state). In this state, microglia proliferate and begin phagocytosing, or engulfing, debris, including amyloid plaques.
A receptor on the surface of microglia, TREM2, is a key molecular switch that controls this DAM state. Since the discovery of TREM2’s role in Alzheimer’s, it has captured significant attention in the field. However, TREM2 is not the only molecular controller of microglia, and many research groups are investigating other controllers of microglial states beyond TREM2.
Dr. Tae-Wan Kim has been studying a molecule called SEMA3A and its ability to dictate microglial states. Interestingly, SEMA3A is produced by neurons and is normally studied for its role in guiding neuronal development. However, Dr. Kim has found that microglia also have SEMA3A receptors, which, when activated, can induce a microglial state similar to DAM, which increases phagocytosis and pro-inflammatory signaling. SEMA3A acts through a pathway that is independent of TREM2 signaling. The Kim lab hypothesizes that SEMA3A functions as a TREM2-independent neuronal signal that can activate microglia by switching them to a DAM state. Defining this pathway could reveal new therapeutic strategies to control neuroinflammation and amyloid clearance in AD.
This project builds on Dr. Kim’s preliminary studies through two experimental aims. In the first, they will define the full extent of SEMA3A’s impact on microglia. They will do this at both a functional and gene expression level. To determine the functional implications, they will look at phagocytosis, inflammatory signaling, and lipid droplet accumulation (a sign that microglia have entered a dysfunctional state). At the gene expression level, they will identify what downstream signaling pathways control the shift in microglial state. Ultimately, this aim focuses on the inflammatory signals microglia release after they have been triggered by SEMA3A. The second aim focuses on how SEMA3A triggers changes in microglia. Dr. Kim’s team will focus on the two microglial SEMA3A receptors: NRP1 and PlexinA1. They will eliminate or reduce the levels of each receptor to determine if one or both receptors are necessary for SEMA3A to induce the DAM-like state. The signaling cascades triggered by these receptors will also be defined.
This project expands the field’s understanding of the molecular mechanisms that control microglial states. By identifying a pathway independent of the well-characterized TREM2 pathway, this project could lead to the discovery of a new therapeutic target for controlling microglia and treating AD.
