The Role of Microglial-specific MyD88-dependent Signaling in Tauopathies

Project Summary

Tauopathies, such as Alzheimer’s disease (AD), are characterized by abnormal functions of microtubule-associated binding protein tau (MAPT). This project focuses on examining how inflammation induced by abnormal MAPT can impact how the disease progresses. Specifically, Dr. Miller will examine how activation of microglia, the immune cells of the brain, contribute to disease development and progression. While previous studies have indicated that altered inflammation and microglial activation in particular contribute to the development of abnormal MAPT, at present the mechanism(s) responsible have yet to be identified and thus cannot be effectively targeted therapeutically.

For this study, Dr. Miller will interrupt the signaling of a critical innate immune system (the first line of defense against bacteria, viruses, or other toxic agents) signaling pathway at both an early and mid-stage point of disease progression in mice with tauopathy. For the first aim, Dr. Miller will examine the biochemical and physical effects of this interruption. The second aim will focus on monitoring changes in markers of inflammation, as well as the differences in the key proteins that are generated with or without disruption of the signaling pathway.

This is the first time that this signaling pathway has been removed specifically from microglia, and will aid in understanding the complex contributions of microglia to disease progression. Once particular molecules and signaling pathways have been identified that influence MAPT pathology, additional pre-clinical studies targeting these molecules will be undertaken. Given the recent failures of the amyloid-based therapies for Alzheimer’s disease, it is imperative to consider other therapeutic targets.