Tauopathies are a group of diverse dementias and movement disorders that are characterized by intracellular accumulations of tau. They include about 20 disorders, including Alzheimerâ€™s disease, Pickâ€™s disease, progressive supranuclear palsy and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Mutation in the tau gene has been shown to cause one of these diseases (FTDP-17). More importantly, tau dysfunction and/or accumulation is believed to cause or contribute to the pathology of all these diseases. A classical pathological hallmark of some of these diseases (neurofibrillary tangles = large aggregates of tau) is now not believed to be the most toxic tau species. But what is the toxic tau species? Why is this important?
Understanding which is the toxic species of tau (which we currently do not know) would help to design specific therapies. In this study, we set out to look for biochemical tau species that would be better candidates for toxic tau species. We used mouse models overexpressing mutant forms of tau that cause neurodegeneration both in mouse models as well as in human subjects.
We have identified a novel tau species, tau multimers, as a possible candidate. Tau multimers were already present at low levels at young age in mouse model of tauopathy before the onset of memory deficits and they were substantially increased at later stages of the pathology. The levels of these species also correlate with the extent of memory deficits at different ages in individual mice. We saw also similar association with toxicity in another mouse model of tauopathy. In summary, we observed correlation between levels of these multimers and toxicity in two different models at various ages.
Is this biochemical species relevant to human diseases? We also observed similar species in brains from human subjects with tauopathies. Most importantly, we never detected this species in brains from non-demented subjects, suggesting a causal relationship. Our studies show that tau multimers are associated with tau toxicity and suggest a possible target for tau-based therapies.