Distinct tau prion strains propagate in cells and mice and define different tauopathies

By David W. Sanders, Sarah K. Kaufman, Sarah L. DeVos, Apurwa M Sharma, Hilda Mirbaha, Aimin Li, Scarlett J. Barker, Alex C. Foley, J. Thorpe, Louise C. Serpell and 4 more. Neuron, 2014

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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.

Subfields: Molecular Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/3d8146ec1338a84ec4933637a9a1204764466a68

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Citations in the corpus

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Some studies have shown that various distinct pathological patterns of tau aggregates can be induced by distinct tau strains from tau transgenic mice or patients with different tauopathies [234, 235, 266, 267].”
Proteopathic tau seeding predicts tauopathy in vivo (2014, background): “Our laboratory has previously failed to demonstrate cross-seeding onto tau-expressing cells using fibrillar synuclein, amyloid β, or expanded huntingtin seeds (20).”
Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein (2015, positive): “tau repeats formed in human embryonic kidney (HEK) 293 cells (85); they could be distinguished upon injection into the brain of presymptomatic transgenic mice, from where they could be pas-”
NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease (2018, positive): “Many in the field are convinced that amyloidosis induces or facilitates the spread of pathologic tau (perhaps by promoting pathologic tau strains [218,219]), pathologic tau is immediately proximate to neurodegeneration, and neurodegeneration is the proximate cause of cognitive decline (C).”
Structure-based Classification of Tauopathies (2021, positive): “When multiple tau seeds are found in a PSP brain (15), this may be indicative of co-pathology.”