Published: 30 September 2026
Prion-like transmission of human tau strains in the mouse brain
Sofia Lövestam, Aki Shimozawa, Airi Tarutani, Reiko Ohtani, Masami Masuda-Suzukake, Kazuko Hasegawa, Andrew C. Robinson, Yuko Saito, Shigeo Murayama, Mari Yoshida, Hisaomi Suzuki, Mitsumoto Onaya, Masato Hasegawa, Michel Goedert & Sjors H. W. Scheres
Nature (2026) Cite this article
Abstract
Most neurodegenerative diseases are thought to spread through the brain by prion-like mechanisms, in which filamentous protein assemblies self-propagate by templated seeding1. Distinct conformations of amyloid filaments may provide the physical basis for the strains that lead to different diseases2. However, a central pillar of the prion hypothesis, that strains retain their structural identity upon transmission, has not been demonstrated. Here we show that the injection of tau filaments from the brains of individuals with Alzheimer’s disease or corticobasal degeneration into the brains of wild-type mice leads to the seeded assembly of amyloid filaments made of mouse tau with the same structures as those of the seeds. Thus, we show that, similar to prion strains, tau filaments propagate through templated seeding, and that the mouse is a suitable model to study the molecular mechanisms by which distinct tau folds drive disease-specific pathology in the brain.
snip…
Discussion We provide evidence for the prion-like transmission of human disease-specific tau strains in the mouse brain. Because the mouseand human tau sequences are identical within the ordered cores of the AD and CBD filament folds, mouse tau assembles into filaments with the same atomic structures as those from human brains. Consistent with previous observations15,17,21,22, and supporting the hypothesis that distinct tau folds represent unique strains, injection of human-brain-derived tau seeds led to cell-type-specific lesions in the mouse brain characteristic of AD and CBD.
Alternative splicing of the MAPT transcript leads to the expression of six tau isoforms in the adult human brain, with three isoforms comprising three microtubule-binding repeats (3R) and three isoforms comprising four repeats (4R)33. Human tauopathies are classified according to the isoform composition of their filaments: a mixture of all six isoforms assembles in 3R + 4R tauopathies such as AD, only 3R tau assembles in 3R tauopathies such as Pick’s disease, and only 4R tau assembles in 4R tauopathies such as CBD. Because adult mice express only 4R tau, the absence of 3R tau represents a species barrier for the transmission of tau seeds with the Pick fold. This barrier does not apply to 3R + 4R and 4R tauopathies. Therefore, tau seeds from other 3R + 4R and 4R tauopathies, such as CTE and progressive supranuclear palsy, may also be transmitted in wild-type mice. Alternatively, mice expressing both 3R and 4R mouse tau34 or mice expressing all six human brain tau isoforms in the absence of endogenous mouse tau22,35,36 can be used to transmit seeds from all human tauopathies, and these mice exhibit more extensive tau pathology than wild-type mice24.
Despite the similarities in how tau and prion strains propagate, important differences exist between the two proteins. Prion diseases are infectious and can be transmitted between individuals, whereas inter-individual transmission of tauopathies has not been reported (although iatrogenic AD has been reported in recipients of cadaveric pituitary-derived growth hormone that contained AD seeds37). It remains to be seen whether the peripheral administration of tau seeds can cause neurodegeneration. Prion diseases typically also progress much faster than tauopathies. Thus, mice injected with prion seeds can develop severe disease4, whereas mice injected with tau seeds appear healthy, despite the presence of tau inclusions in the brain14. It is possible that mice injected with tau seeds do not live long enough to develop symptoms, or that the amount of tau inclusions that form in these mice is not sufficient to lead to clinical symptoms. It therefore remains unknown whether tau seed propagation and downstream toxicity occur in two separate phases, as has been suggested for prions38. Mice that are transgenic for human tau with mutations that cause frontotemporal dementias spontaneously form abundant tau filaments and develop severe neurodegeneration39,40,41,42. Moreover, rhesus macaques injected with tau seeds from the brains of individuals with the 4R tauopathy progressive supranuclear palsy developed motor and behavioural impairments 6 months after seed injection43.
Filament assembly can be separated into three stages. The first stage involves seed uptake, which may involve cell surface receptors13,44,45 and is probably influenced by the size of tau filaments and their surface properties, including the presence or absence of a fuzzy coat. The second stage consists of the recruitment and templated conversion of monomeric tau within the recipient cell46. This step requires compatibility between the seed, the monomeric tau substrate, including its post-translational modifications, and the cell-type environment, which may or may not comprise cofactors that are essential for filament assembly. During this stage, the human tau seeds disappear progressively, indicating that faithful templating and clearing of tau seeds are co-occurring in brain cells. The third and final stage is the release of the newly formed filaments and their uptake by connected cells, resulting in the stereotypical spread of tau pathology through connected brain regions47. Different tau folds may influence one or more of these stages, thereby shaping both the efficiency of propagation and the cell-type specificity observed across tauopathies.
Identifying the molecular factors that modulate tau uptake, templated conversion and propagation is essential for understanding how distinct tau strains transmit specific pathologies in a prion-like manner. Future serial passage experiments will provide a complete characterization of disease-specific tau strains. Our observation that the intracerebral injection of wild-type mice with tau seeds from human brains with neurodegenerative diseases leads to the assembly of mouse tau filaments that retain the conformation of the human disease-specific seeds indicates that the mouse is a suitable model for investigating these mechanisms. This explanation will lead to a better understanding of disease-specific tau strain behaviour and provide new diagnostic and therapeutic avenues.
https://www.nature.com/articles/s41586-026-11061-x.pdf
Saturday, February 18, 2023
TAUOPATHIES, PICKS, AND PRIONS
https://tauopathies.blogspot.com/2023/
https://tauopathies.blogspot.com/2017/06/
https://tauopathies.blogspot.com/2013/05/
https://tauopathies.blogspot.com/2013/06/spreading-of-tau-pathology-in.html
Singeltary 2001, CJD or Alzheimer's or the same ???
To: BSE-L@uni-karlsruhe.de
I have always wondered if CJD and or all TSEs and Alzheimer's could be linked. i have been of the opinion that Alzheimer's is a TSE for a long time, just at the low end of the titre of infectivity…end
Singeltary 2001, CJD or Alzheimer's or the same ???
To: BSE-L@uni-karlsruhe.de
I have always wondered if CJD and or all TSEs and Alzheimer's could be linked. i have been of the opinion that Alzheimer's is a TSE for a long time, just at the low end of the titre of infectivity…end
Singeltary wayback;
“There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread.”
O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?
Re-Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)
snip...see full Singeltary Nature comment here;
Alzheimer's disease
let's not forget the elephant in the room. curing Alzheimer's would be a great and wonderful thing, but for starters, why not start with the obvious, lets prove the cause or causes, and then start to stop that. think iatrogenic, friendly fire, or the pass it forward mode of transmission. think medical, surgical, dental, tissue, blood, related transmission. think transmissible spongiform encephalopathy aka tse prion disease aka mad cow type disease...
Commentary: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic,
what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic,
what if ?
Background
Alzheimer’s disease and Transmissible Spongiform Encephalopathy disease have both been around a long time, and was discovered in or around the same time frame, early 1900’s. Both diseases are incurable and debilitating brain disease, that are in the end, 100% fatal, with the incubation/clinical period of the Alzheimer’s disease being longer (most of the time) than the TSE prion disease. Symptoms are very similar, and pathology is very similar.
Methods
Through years of research, as a layperson, of peer review journals, transmission studies, and observations of loved ones and friends that have died from both Alzheimer’s and the TSE prion disease i.e. Heidenhain Variant Creutzfelt Jakob Disease CJD.
Results
I propose that Alzheimer’s is a TSE disease of low dose, slow, and long incubation disease, and that Alzheimer’s is Transmissible, and is a threat to the public via the many Iatrogenic routes and sources. It was said long ago that the only thing that disputes this, is Alzheimer’s disease transmissibility, or the lack of. The likelihood of many victims of Alzheimer’s disease from the many different Iatrogenic routes and modes of transmission as with the TSE prion disease.
Conclusions
There should be a Global Congressional Science round table event set up immediately to address these concerns from the many potential routes and sources of the TSE prion disease, including Alzheimer’s disease, and a emergency global doctrine put into effect to help combat the spread of Alzheimer’s disease via the medical, surgical, dental, tissue, and blood arena’s. All human and animal TSE prion disease, including Alzheimer’s should be made reportable in every state, and Internationally, WITH NO age restrictions. Until a proven method of decontamination and autoclaving is proven, and put forth in use universally, in all hospitals and medical, surgical arena’s, or the TSE prion agent will continue to spread. IF we wait until science and corporate politicians wait until politics lets science _prove_ this once and for all, and set forth regulations there from, we will all be exposed to the TSE Prion agents, if that has not happened already.
end...tss
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
https://journals.plos.org/plosone/article/comment?id=10.1371/annotation/933cc83a-a384-45c3-b3b2-336882c30f9d
https://creutzfeldt-jakob-disease.blogspot.com/2023/09/professor-john-collinge-on-tackling.html
terry
