The aggregation of the protein tau is associated with a wide variety of neurodegenerative diseases, including Alzheimer's disease (AD). It has proven extraordinarily difficult to develop therapeutic strategies against AD and AD-related disorders that modify the underlying pathologies associated with them. Because it would be impractical to screen potential drugs against aggregates purified from disease brain tissue due to the large amounts of materials that would be required, most studies employ tau aggregates that have been induced artificially. Recent results have shown that the tau aggregates associated with disease have specific three dimensional structures, and that one of the most commonly used inducers to generate tau aggregates for therapeutic screening have a structure dissimilar from those found in disease. It is therefore critical for the field to identify conditions that can generate tau aggregates that have structural similarity to authentic aggregates from disease. We will take the approach of combining a wide variety of biochemical inducers with a number of different tau variants that we predict will generate a disease-relevant strain. We will compare the strains we generate with those we purify from AD and AD related neurodegenerative disorders such as progressive supranuclear palsy. If we are successful in identifying an artificial disease-relevant strain, we will continue our screening efforts to identify disease-relevant tau aggregation inhibitors while simultaneously working toward building a library of tau aggregate strains for multiple neurodegenerative tauopathies. These efforts will not only greatly increase the probability of generating effective therapeutics, but could also provide the possibility for creating molecular probes for the detection and diagnosis of specific tau strains in disease.
Alzheimer's disease and Alzheimer's disease related dementias affect more than 5 million Americans at a total health care cost of more than $250 billion. These diseases lack any effective treatments that modify the underlying pathology. This proposal will develop desperately needed resources that will enable the screening of potential therapeutics against disease-relevant protein aggregates.
