The role of microglia in brain resilience to pathological protein aggregates

Normal aging and neurodegenerative disease are typically characterized by accumulation of waste products inside the brain and in particular by aggregation of various types of proteins like Amyloid-beta outside of cells or the proteins Tau, alpha-synuclein, and TDP-43 inside cells. These observations are so characteristic that some of them have elevated to the defining features of diagnosing a particular condition such as Alzheimer's disease. Patients that carry mutations in these genes have an increased risk to develop age-associated neurodegeneration which demonstrates that these aggregation-prone proteins must somehow trigger neurodegeneration. But, importantly, on the other hand, it is also clear that these protein aggregations alone are not toxic because they can exist in people that have no sign of neurodegeneration whatsoever. Therefore, the brain must have evolved mechanisms that make the brain resilient to these age-associated changes and disease progresses only when these resilience factors are exhausted. 

This project proposes to investigate the mechanisms of brain resilience to the spreading and aggregation of disease proteins. Using sophisticated 2-dimensional and 3-dimensional human stem cell models mimicking the cellular composition of the brain, the team will define the role of the brain's immune cells in conferring this resilience.