Understanding How an Innate Immune Signaling Pathway in Microglia Affects Different Stages of Tau Pathology

Crystal M Miller, PhD
The Cleveland Clinic Foundation (Cleveland, OH)
Year Awarded:
Grant Duration:
July 1, 2013 to June 30, 2015
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

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


Bruce T. M Lamb, Ph.D.
Cleveland Clinic Lerner Research Institute


In Alzheimer's Disease (AD) and other tauopathies, in which tau protein accumulates abnormally in neurons, inflammation is thought to negatively contribue to pathology. Since it is known that microglia (brain immune cells that migrate to areas of damage) regulate inflammation, the team of Drs. Lamb and Miller has developed a model in which they can test the specific contribution of microglia to disease progression at different stages of AD. This project seeks to determine whether a particular signaling pathway in microglia is harmful or helpful. The identification of the contribution of this pathway and others will suggest novel therapeutic targets for tauopathies.


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.

About the Researcher

Dr. Miller is a Postdoctoral Research Fellow at the Cleveland Clinic Foundation. She earned her doctorate in Neurosciences from Case Western Reserve University studying motor axon guidance in the fruit fly. She currently works in the lab of Dr. Bruce Lamb where she focuses on the connection between neuroinflammation and Alzheimer’s disease. Her research utilizes a variety of genetic mouse models to identify the roles of different cell types in the development and progression of disease pathology.