Distinct Tau Prion Strains Propagate in Cells and Mice and Define Different Tauopathies

Abstract

Summary Prion-like propagation of tau aggregation may underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations (“strains”) in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naïve cells re-establishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice re-creates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This may explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.

P2‐241: Focal Temporal Pole Atrophy and Network Degeneration in Semantic Variant Primary Progressive Aphasia

“…Supporting this hypothesis, laboratory evidence has shown that disease proteins can travel through local and long-range pathways via transynaptic spread (Frost et al, 2009;Palop and Mucke, 2010;Sanders et al, 2014). Although the relationship between the strength of functional connectivity and underlying white matter integrity is still being examined (Honey et al, 2009;Van Den Heuvel et al, 2009;Hermundstad et al, 2013), the results of our rs-fcMRI analysis are broadly consistent with previously reported patterns of white matter degeneration in svPPA (Acosta-Cabronero et al, 2011;Agosta et al, 2012;Iaccarino et al, 2015).…”

Proteopathic tau seeding predicts tauopathy in vivo

“…Our laboratory previously demonstrated that template-based seeding requires homotypic interactions between seed and substrate (20), consistent with the existence of seeding barriers (33). To test the specificity of our assay, we conducted cross-seeding experiments with the tau biosensor line and measured FRET responses.…”

“…In vivo studies have described tau protein spreading from local sites to distant regions, presumably via transsynaptic movement (11,12,(17)(18)(19). Finally, our laboratory and another recently demonstrated that tau propagates discrete amyloid conformations through the brains of animals that give rise to unique neuropathologies (18,20).…”

“…In vivo studies have described tau protein spreading from local sites to distant regions, presumably via transsynaptic movement (11,12,(17)(18)(19). Finally, our laboratory and another recently demonstrated that tau propagates discrete amyloid conformations through the brains of animals that give rise to unique neuropathologies (18,20).Despite this evidence, it remains unclear whether the development of proteopathic tau seeding represents a causal process of tauopathy, a downstream consequence of tau fibril accumulation, a coincident trait of neurodegeneration, or even an epiphenomenon. If proteopathic seeds are indeed a causal agent of disease, then their activity should exist in the brains of tauopathy mouse models and human subjects, precede other forms of pathology, and correlate with disease progression.…”

Untangling the tauopathies: Current concepts of tau pathology and neurodegeneration

“…The concept of different 'strains' of tau aggregates is consolidated by animal studies demonstrating that the intracerebral injection of brain homogenates from humans with pathologically confirmed PSP, CBD and AGD produced distinct lesions in mouse brains similar to those of the respective human tauopathies [13]. Tau aggregates from different tauopathies from human brain tissue exhibited distinct confirmations or 'strains' and the proteopathic seeds can be transmitted into transgenic mouse brains and be re-introduced to naïve cells to replicate the same structural phenotype and manifest distinct pathological phenotypes [15]. These animal studies support the notion that a 'prion-like' templating mechanism is central to the disease progression in tauopathies [16,17].…”