Evaluating the role of immune cells in the brain and a related protein, TREM2, on Alzheimer’s disease pathology

Project Summary

Aggregation of the tau protein in the brain is a hallmark of Alzheimer’s disease (AD), and the propagation of aggregated tau protein is strongly associated with the degeneration and dementia. In addition, brain immune cells, known as microglia, play a crucial role in AD and the propagation of tau pathology in the brain. Indeed, mutations in TREM2, a protein found on microglia, are one of the strongest genetic risk factors for AD. Therefore, we will investigate if decreasing microglia or TREM2 levels in the brain can modulate tau propagation. While research on microglia and TREM2 in AD has largely focused on their interactions with Aβ pathology, some evidence suggests that microglia and TREM2 can directly affect tau propagation in the brain. Because progression of tau pathology into the limbic and neocortex coincides with cognitive impairment in AD, it is essential to better understand how tau pathology seeds and spreads throughout the brain of AD patients. In this project, I propose to evaluate the impact of microglia and TREM2 on tau seeding and spreading by depleting microglia or deleting TREM2 in the brains of mouse models with or without amyloid pathology and to investigate the mechanisms underlying the effects of microglia or TREM2 removal on tau propagation. Taken together, these studies will help us to identify unique therapeutic strategies to modulate the propagation of tau pathology in the brain of AD patients by targeting microglia or TREM2.