The Role of Tau Strains in Generating the Diversity of Human Tauopathies

Neurodegenerative tauopathies are characterized by the abnormal accumulation of tau protein inside neural cells. The most common neurodegenerative disease, Alzheimer’s disease (AD), is one such tauopathy, in which tau tangles contribute to both the neurodegeneration and clinical progression of the disease. In other tauopathies like corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau inclusions are the most prominent neuropathological feature, solely contributing to the clinical symptoms and disease progression in those patients. Yet, tauopathies are highly diverse, with distinct clinical features and neuropathological lesions, despite the common aggregation of tau protein. One hypothesis that has emerged in the field is that misfolded tau protein can acquire multiple different structural conformations, known as tau strains, which differentiate unique tauopathies. This dissertation will test the hypothesis that tau strains derived from human tauopathy brains underlie the diversity of tauopathies. First, I describe a novel mouse model utilizing human post-mortem brain-derived tau aggregates to seed tau pathology in nontransgenic (nonTg) mouse brain (Chapter 2). Then I describe using this nonTg mouse model to show tau strains derived from different human tauopathy brains have distinct seeding potencies and cell-type specificities that recapitulate the diversity of tauopathies (Chapter 3). From this study, I found a unique spatiotemporal transmission of glial tau pathology following injection of certain tau strains. Therefore, I examine the novel relationships between neuronal and glial tau in seeding and spreading tau pathology in the mouse brain in Chapter 4. This dissertation demonstrates tau strains do exist in human tauopathy brains, and they play a key role in generating the unique neuropathologies of different tauopathies