Alzheimer’s Disease Tau Consortium: Strain Replication in Mouse and Cell Models

The accumulation of pathological tau protein assemblies (aggregates) leads to neuron dysfunction and death. Tau protein forms distinct assembly structures that lead to different patterns of disease in AD and related disorders. While therapies and diagnostics will be based on detecting pathological tau, and targeting it for degradation, it is relatively difficult to discriminate the different forms of tau assemblies. Cryogenic electron microscopy (cryo-EM) has been used to determine these structures, but it requires large amounts of brain tissue and specialized facilities. Additionally, the difficulty of reproducing pathological tau structures in experimental systems hampers progress. We have exploited simple cell systems to develop methods to rapidly and accurately discriminate the different forms of tau. In preliminary work, we determined that some neurodegenerative diseases have evidence of multiple forms of tau, especially the structure associated with AD. This has important therapeutic implications, especially if agents only target one form when two are present. Here, we will use cryo-EM and advanced cell studies to test whether this is true. We will also test whether it is possible to replicate the pathological structure of tau from AD and related disorders in simple cells and a mouse model that expresses human tau. This would greatly advance our ability to develop more effective treatments for AD patients.