Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer's-Like Tauopathy

Iba, Michiyo; Guo, Jing; McBride, Jennifer D.; Zhang, Bin; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1523/jneurosci.2642-12.2013

Cited by 565 publications

(646 citation statements)

References 45 publications

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“…Similarly, recombinant human 2N4R tau with the P301S mutation, and K18 with the P301L mutation, were fibrillized in the presence of heparin and inoculated into young PS19 mice (human 1N4R tau with the P301S mutation) (51). Both of these 4R-containing fibrils induced tau neuropathology, whereas inoculation of α-synuclein fibrils had no effect, highlighting homotypic propagation of synthetic 4R tau prions in a third mouse model (40).…”

Section: Discussionmentioning

confidence: 99%

“…Measuring the kinetics of PrP Sc and MSA propagation following intracerebral injection into Tg mice has been important in discerning the underlying biology of these prions. However, although intracerebral injection of tau fibrils into Tg mice expressing tau transgenes resulted in tau neuropathology, such experiments were inconclusive with respect to assessing the kinetics and accumulation of tau prions (40)(41)(42)(43)(44). Instead, measurements made from cells expressing the tau-YFP fusion proteins (31,32,45) have been more informative.…”

Section: Discussionmentioning

confidence: 99%

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Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Woerman

Aoyagi

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

149

130

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Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer's disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R-or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts.argyrophilic grain disease | corticobasal degeneration | Pick's disease | progressive supranuclear palsy | tauopathies

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Woerman

Aoyagi

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

149

130

View full text Add to dashboard Cite

show abstract

“…Mild induction of Tau deposition was also obtained in non-Tg mice inoculated with human tauopathy brain material (75). As with A␤, recombinant Tau fibrils are sufficient to accelerate Tau deposition in Tg mice expressing mutant Tau (76). Arguably, the most convincing demonstration of the prion-like behavior of a non-PrP protein has been provided with ␣-synuclein.…”

Section: Mouse Models For Studying the Expanding Universe Of Prion DImentioning

confidence: 93%

Mouse Models for Studying the Formation and Propagation of Prions

Watts

Prusiner

2014

Journal of Biological Chemistry

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Prions are self-propagating protein conformers that cause a variety of neurodegenerative disorders in humans and animals. Mouse models have played key roles in deciphering the biology of prions and in assessing candidate therapeutics. The development of transgenic mice that form prions spontaneously in the brain has advanced our understanding of sporadic and genetic prion diseases. Furthermore, the realization that many proteins can become prions has necessitated the development of mouse models for assessing the potential transmissibility of common neurodegenerative diseases. As the universe of prion diseases continues to expand, mouse models will remain crucial for interrogating these devastating illnesses.

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“…This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates-or seeds-serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

Proteopathic tau seeding predicts tauopathy in vivo

Holmes

Furman

Mahan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

522

792

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Transcellular propagation of protein aggregates, or proteopathic seeds, may drive the progression of neurodegenerative diseases in a prion-like manner. In tauopathies such as Alzheimer's disease, this model predicts that tau seeds propagate pathology through the brain via cell-cell transfer in neural networks. The critical role of tau seeding activity is untested, however. It is unknown whether seeding anticipates and correlates with subsequent development of pathology as predicted for a causal agent. One major limitation has been the lack of a robust assay to measure proteopathic seeding activity in biological specimens. We engineered an ultrasensitive, specific, and facile FRET-based flow cytometry biosensor assay based on expression of tau or synuclein fusions to CFP and YFP, and confirmed its sensitivity and specificity to tau (∼300 fM) and synuclein (∼300 pM) fibrils. This assay readily discriminates Alzheimer's disease vs. Huntington's disease and aged control brains. We then carried out a detailed time-course study in P301S tauopathy mice, comparing seeding activity versus histological markers of tau pathology, including MC1, AT8, PG5, and Thioflavin S. We detected robust seeding activity at 1.5 mo, >1 mo before the earliest histopathological stain. Proteopathic tau seeding is thus an early and robust marker of tauopathy, suggesting a proximal role for tau seeds in neurodegeneration.amyloid | neuropathology | dementia | aging P rotein aggregation characterizes many neurodegenerative disorders, including Alzheimer's disease (AD) and the related tauopathies. These disorders feature the accumulation of fibrillar deposits of the microtubule-associated protein tau with progressive deterioration of the central nervous system. Tau pathology and its associated brain atrophy do not appear randomly throughout the brain, but rather progress along distinct neural networks (1-5). This aspect suggests a role for transcellular spread of a pathogenic agent via neural connections. Our laboratory and others have previously hypothesized that tau aggregates-or seeds-serve as this agent of spread, transmitting the aggregated state from cell to cell via prion-like mechanisms (6-15).Mounting fundamental insights support this hypothesis. Tau seeds applied to the outside of cells bind the cell surface by attaching to heparan sulfate proteoglycans, triggering uptake by macropinocytosis (13). Upon internalization, tau seeds nucleate the fibrillization of endogenous tau monomer via templated conformational change, or seeding (8, 10). Tau seeding requires a critical unit of size for activity, as only particular species propagate the aggregated state (16). 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 wheth...

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Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer's-Like Tauopathy

Cited by 565 publications

References 45 publications

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

Mouse Models for Studying the Formation and Propagation of Prions

Proteopathic tau seeding predicts tauopathy in vivo

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