A Human Brain-in-a-Dish Model to Investigate Disease Mechanisms of FTD
1. We will use CRISPR to introduce synergistic Tau mutations into stem cells, differentiate into human brain cells, and culture them as 2- and 3-dimensional brain tissue models. 2. We will characterize pathology with a focus on Tauopathy. 3. We will investigate disease-related changes in brain tissue models to understand effects of pathology on neurons, and influences of Tau splicing, non-neuronal brain cell types, or genetic risk factors on pathogenesis. We will also develop a chimeric human/mouse in vivo model and set up assays for drug discovery.
Our human brain tissue model will allow investigating human-specific disease mechanism, which is hardly possible in mouse models.Unlike mouse and existing stem cell models, our model recapitulates adult Tau splicing, which plays a central role in pathogenesis. Preliminary data show that our model is the first to reproducibly show misfolding, seed production and aggregation of endogenous Tau without artificial modifications, such as overexpression. Our model will provide novel insights into human-specific disease mechanisms, and – as it recapitulates typical late-stage phenotypes, such as seed formation, Tau misfolding and aggregation – allow new drug discovery approaches.