Tau Seeding in Health and Disease

An abundance of evidence supports that the protein tau adopts a wide variety of conformations with the ability to self-assemble and propagate in living systems, and that this prion behavior may drive neurodegeneration in tauopathies. However, the inciting events that lead to tau seed formation and aggregation are unknown. It remains possible that tau can act as a prion outside the context of disease, as part of its normal function, and the accumulation of tau prions in neurodegenerative diseases reflects a loss of control of this normal function. During my dissertation research, I completed a series of investigations on tau's ability to form seeds outside the context of classical tauopathies. I discovered that tau seeds are present in the cerebral cortex of healthy individuals. Tau seeds form in a region and species specific manner, being absent in the cerebellum of healthy individuals and undetectable in murine models. Seeding in healthy individuals was independent of age, implying it is not a result of emerging tauopathy but rather, that prion formation is a normal aspect of tau biology. This may be related to its interactions with RNA. I also surveyed for tau seeding in several inflammatory diseases with neurodegenerative components that have been reported to exhibit tau accumulation based on immunohistochemistry. I found seeds at levels beyond that of healthy individuals in temporal lobe epilepsy as well as multiple sclerosis. Thus, tau may be a target of many convergent pathways that lead to neurodegeneration. The work here highlights the significant role that tau plays in human health and disease. Further understanding of how normal biological processes, as well as inflammation, affect tau's prion state will be essential for the development of therapeutic strategies for the prevention and treatment of tauopathies.