Defining the Role of Microglial Tau in 4R tauopathies

Pathway Grant

Principal Investigator: Dr. Abhirami Iyer, Washington University School of Medicine

Microglia are the brain’s immune cells and play a complex role in 4-repeat tauopathies, a group of neurodegenerative diseases that includes frontotemporal lobar degeneration-tau and progressive supranuclear palsy. These cells help protect the brain by cleaning up tau protein from damaged neurons, but they can also contribute to disease progression by releasing more tau and causing inflammation.

We believe that microglia from patients with 4-repeat tauopathies undergo changes that affect how they function. Our recent research shows that these cells can produce tau on their own. We also found that a mutation in the gene called MAPT that is linked to frontotemporal lobar degeneration-tau, can trigger these changes in microglia.

To investigate how these changes impact microglial function in both genetic and sporadic cases of 4-repeat tauopathies, we plan to create microglia-like cells from patients' stem cells to achieve three main goals:

Aim 1: We want to understand how genetic and sporadic conditions affect the behavior of microglia and how these changes impact healthy neurons.

Aim 2: We will explore whether tau protein is necessary for these changes, which could help us identify specific microglial responses that might lead to new treatments.

Aim 3: We plan to use antibodies that target a microglial receptor called TREM2 to enhance its signaling and potentially repair the defects in microglia associated with these diseases.

Recent evidence suggests a strong connection between tau and microglial function, but this area needs more research. Our innovative approach, using stem cells from patients, aims to provide insights that could inform current and future clinical trials focusing on tau and TREM2 in neurodegenerative diseases.