Modification of tau pathology by yeast prion seeding and tau oligomer expression

Neurodegenerative disorders are a mayor health risk for the aging population of the world. The aggregation of tau constitutes a mayor hallmark of Alzheimer disease (AD) and other neurological diseases such as progressive supranuclear palsy, corticobasal degeneration, and frontotemporal dementias with parkinsonism liked to chromosome 17. Tau spreads in a prion like manner via the formation of disease specific fibrils. The cause of tau aggregation in neurodegenerative disorders has yet remained unclear. We were now able to show, that the archaic yeast prion domain Sup35NM is able to cross-species cross-seed human tau. In tau transgenic P301S mice this led to an accentuation of tau pathology in the hippocampus of Sup35NM inoculated mice. In vitro seeding of tau monomers with Sup35NM fibrils led to the accelerated formation of tau fibrils. These fibrils showed a characteristic corkscrew-like pattern. In AD, early tau aggregation occurs in the olfactory bulb. The nasal sensors are in close contact to exogenous agents and the microbiome present in the nasopharyngeal cavity, and they are anatomically connected to the limbic system, which is also affected early in AD. Together our results allow a novel perception of the prion world, in which archaic prions of the human microbiome are able to influence the aggregation of prion-like proteins like tau in neurodegenerative diseases. Understanding the initiation of prion formation in sporadic neurodegenerative disorders will be pivotal for the long-awaited generation of preventive or curative approaches for these devastating disorders. Another important aspect concerning the desired treatment of neurodegenerative diseases like tauopathies is the potential long term effect of neurotoxic stress caused by misfolded proteins like tau. We therefore investigated the long term effects of severe early neurotoxic tau stress in recovered transgenic P301SxTau62 mice. Counterintuitively, P301SxTAU62 tau mice which underwent transient severe paralysis in early life, and maintained their ...