Identifying the Mechanisms That Underlie Tau Aggregation and Neurotoxicity

To use CRISPR-based screening techniques and human histopathologic analysis to elucidate the mechanisms that underlie tau aggregation and neurotoxicity across different tauopathies.

Alzheimer’s disease and frontotemporal dementia feature the accumulation of misfolded, aggregated tau protein in neurons that are lost early in the course of these diseases. The mechanisms that underlie tau misfolding and accumulation, and its associated neurotoxicity, are not known. This project employs whole-genome screening techniques to identify the cellular pathways that regulate tau aggregation and toxicity in human-induced pluripotent stem cell-derived neurons. This work will provide critical insight into tau-associated disease mechanisms and identify potential therapeutic targets for Alzheimer’s and frontotemporal dementia.

This proposal combines high-throughput CRISPR-based screening techniques with a novel iNeuron model system that can amplify full-length tau aggregates. This novel model system can amplify distinct tau aggregate strains seeded from different human tauopathies, which increases the likelihood that it will recapitulate the relevant pathophysiology that underlies these diseases. This model also provides a powerful tool to identify mechanisms that underlie tau aggregation or toxicity in human neurons, which can then be examined using in-depth histopathologic analysis in human post-mortem samples.

Different tauopathies are associated with distinct tau aggregation conformations (“strains”), which are hypothesized to underlie the different patterns of pathology and selective vulnerability observed in these diseases. This work will provide important insights into the mechanisms that underlie tau aggregation and neurotoxicity across distinct tau strains. In addition to this mechanistic insight, this research will identify potential therapeutic targets that may slow or prevent the progression of tau aggregation.