Characterization of Tau Oligomeric Strains: Implications for Disease Phenotypes

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Abstract

Neurodegenerative diseases are prevalent, costly and debilitating conditions that are commonly characterized by the aggregation of tau protein. While original studies of Alzheimer’s disease noted the presence of tau aggregated into large, insoluble fibrillar structures known as neurofibrillary tangles, our lab and others found that small, oligomeric aggregates are likely the most toxic species. I found that toxic tau oligomers are elevated in progressive supranuclear palsy, traumatic brain injury and synucleinopathy models and reversal of toxicity can be achieved with treatment of a tau oligomer-specific monoclonal antibody. Tau oligomers have prion-like properties, enabling them to seed the misfolding and aggregation of natively folded, functional tau protein endogenous in the brain. Moreover, the spread of pathology from early affected regions to unaffected areas may be driven by propagation of tau oligomers. However, tau oligomers are not a homogenous population and the formation of different prion-like strains may underlie diversity of pathophysiology in different diseases. In this series of experiments, I have shown that tau oligomeric strains can be prepared in the laboratory and isolated from human disease brain tissue. Brain-derived tau oligomeric strains seed the aggregation of tau in vitro and display distinguishable characteristics based on techniques from the prion field. For the first time, I show that tau oligomeric strains can enter the brain when injected in the eye in mice and induce diverse outcomes. These results lay a critical foundation for the identification of specific tau oligomeric strains and combinations of strains that could be used as biomarkers for different neurodegenerative diseases. Moreover, these results could be used for future development of personalized therapeutics against neurodegenerative disorders by specifically targeting the most toxic strains initiating disease in different individuals.

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Neurodegenerative disease, tau
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