In this project, Dr. Prusiner proposes to insert two versions of the human gene for tau protein into the same lab rats. Tau is a normal protein important in the function of brain cells. It forms toxic clumps in patients with Alzheimer’s disease, progressive supranuclear palsy (PSP), frontotemporal dementia, post-traumatic encephalopathy and a handful of other degenerative diseases. One of the two versions to be inserted is the normal human gene for tau. The other is the human form with mutation that has been found in a few people with frontotemporal dementia. The two genes will be inserted into the rats’ cells in a way that allows them to be turned on and off by the experimenter. This allows for more precise and rapid testing of large numbers of new drugs that may slow or halt the progression of the tau-based diseases. These rats will also provide an excellent animal model for testing new compounds that would stick to aggregates of tau, allowing PET scanning to serve as a diagnostic test for tau disorders. A sensitive and reliable imaging test for the tauopathies would facilitate new drug development and permit diagnosis of human patients at an earlier stage, when a drug response is more likely.

Tau aggregates can accumulate alone, as in the primary tauopathies like PSP, or in concert with other peptide aggregates in other diseases. Tau aggregates have been found with amyloid β (Aβ) in Alzheimer’s disease (AD) and also with an abnormal form of the prion protein in familial Creutzfeldt-Jakob disease (CJD). After the centrality of tau was established in PSP and CBD, a series of incisive studies demonstrated that abnormally folded tau protein molecules act like prion protein in that they cause normal tau molecules to misfold into the same toxic form. Tau prions spread throughout the brain as a chain reaction, analogous to PrPSc and Aβ prions that cause CJD and AD, respectively. The ability to quantify tau prions in all of the tauopathies offers new paradigms for early diagnosis and effective therapeutic intervention.