Peng, C., Trojanowski, J. Q. & Lee, V. M.-Y. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).Article
CAS
PubMed
PubMed Central
Google Scholar
Collinge, J. & Clarke, A. R. A general model of prion strains and their pathogenicity. Science 318, 930–936 (2007).Article
ADS
CAS
PubMed
Google Scholar
Benestad, S. L. & Telling, G. C. in Handbook of Clinical Neurology Vol. 153 (eds Pocchiari, M. & Manson, J.) 135–151 (Elsevier, 2018).Prusiner, S. B. Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Alam, P. et al. Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer. Acta Neuropathol. 148, 56 (2024).Article
PubMed
PubMed Central
Google Scholar
Hoyt, F. et al. Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains. Nat. Commun. 13, 4005 (2022).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Kraus, A. et al. High-resolution structure and strain comparison of infectious mammalian prions. Mol. Cell 81, 4540–4551.e6 (2021).Article
CAS
PubMed
Google Scholar
Manka, S. W. et al. A structural basis for prion strain diversity. Nat. Chem. Biol. 19, 607–613 (2023).Article
CAS
PubMed
PubMed Central
Google Scholar
Manka, S. W. et al. 2.7 Å cryo-EM structure of ex vivo RML prion fibrils. Nat. Commun. 13, 4004 (2022).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Goedert, M., Crowther, R. A., Scheres, S. H. W. & Spillantini, M. G. Tau and neurodegeneration. Cytoskeleton 81, 95–102 (2024).Article
CAS
PubMed
Google Scholar
Shi, Y. et al. Structure-based classification of tauopathies. Nature 598, 359–363 (2021).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Scheres, S. H. W., Ryskeldi-Falcon, B. & Goedert, M. Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids. Nature 621, 701–710 (2023).Article
ADS
CAS
PubMed
Google Scholar
Frost, B., Jacks, R. L. & Diamond, M. I. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845–12852 (2009).Article
CAS
PubMed
PubMed Central
Google Scholar
Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).Article
CAS
PubMed
PubMed Central
Google Scholar
Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl Acad. Sci. USA 110, 9535–9540 (2013).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Boluda, S. et al. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol. 129, 221–237 (2015).Article
CAS
PubMed
Google Scholar
Guo, J. L. et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J. Exp. Med. 213, 2635–2654 (2016).Article
CAS
PubMed
PubMed Central
Google Scholar
Iba, M. et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J. Neurosci. 33, 1024–1037 (2013).Article
CAS
PubMed
PubMed Central
Google Scholar
Iba, M. et al. Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC’s afferent and efferent connections. Acta Neuropathol. 130, 349–362 (2015).Article
CAS
PubMed
PubMed Central
Google Scholar
Narasimhan, S. et al. Human tau pathology transmits glial tau aggregates in the absence of neuronal tau. J. Exp. Med. 217, e20190783 (2020).Article
PubMed
PubMed Central
Google Scholar
Narasimhan, S. et al. Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J. Neurosci. 37, 11406–11423 (2017).Article
CAS
PubMed
PubMed Central
Google Scholar
He, Z. et al. Transmission of tauopathy strains is independent of their isoform composition. Nat. Commun. 11, 7 (2020).Article
ADS
CAS
PubMed
Google Scholar
He, Z. et al. Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018).Article
CAS
PubMed
Google Scholar
Kasen, A. et al. Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency. Nat. Commun. 16, 9240 (2025).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Schweighauser, M. et al. Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau. Acta Neuropathol. Commun. 11, 160 (2023).Article
CAS
PubMed
PubMed Central
Google Scholar
Zhao, W. et al. Cryo-EM structures reveal variant tau amyloid fibrils between the rTg4510 mouse model and sporadic human tauopathies. Cell Discov. 10, 27 (2024).Article
CAS
PubMed
PubMed Central
Google Scholar
Burger, D. et al. Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology. Nature 648, 409–417 (2025).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Yoshida, M. Astrocytic inclusions in progressive supranuclear palsy and corticobasal degeneration. Neuropathology 34, 555–570 (2014).Article
CAS
PubMed
Google Scholar
Gibbons, G. S. et al. Detection of Alzheimer disease (AD)-specific tau pathology in AD and NonAD tauopathies by immunohistochemistry with novel conformation-selective tau antibodies. J. Neuropathol. Exp. Neurol. 77, 216–228 (2018).Article
CAS
PubMed
PubMed Central
Google Scholar
Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Falcon, B. et al. Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol. 136, 699–708 (2018).Article
CAS
PubMed
PubMed Central
Google Scholar
Zhang, W. et al. Novel tau filament fold in corticobasal degeneration. Nature 580, 283–287 (2020).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526 (1989).Article
CAS
PubMed
Google Scholar
Hosokawa, M. et al. Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms. Brain 145, 349–361 (2022).Article
PubMed
Google Scholar
Andorfer, C. et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 86, 582–590 (2003).Article
CAS
PubMed
Google Scholar
Saito, T. et al. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J. Biol. Chem. 294, 12754–12765 (2019).Article
CAS
PubMed
PubMed Central
Google Scholar
Banerjee, G. et al. Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone. Nat. Med. 30, 394–402 (2024).Article
CAS
PubMed
PubMed Central
Google Scholar
Sandberg, M. K., Al-Doujaily, H., Sharps, B., Clarke, A. R. & Collinge, J. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470, 540–542 (2011).Article
ADS
CAS
PubMed
Google Scholar
Allen, B. et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351 (2002).Article
CAS
PubMed
PubMed Central
Google Scholar
Götz, J., Chen, F., Barmettler, R. & Nitsch, R. M. Tau filament formation in transgenic mice expressing P301L tau. J. Biol. Chem. 276, 529–534 (2001).Article
PubMed
Google Scholar
Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405 (2000).Article
CAS
PubMed
Google Scholar
Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).Article
CAS
PubMed
Google Scholar
Darricau, M. et al. Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates. Brain 146, 2524–2534 (2023).Article
PubMed
PubMed Central
Google Scholar
Guo, J. L. & Lee, V. M.-Y. Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem. 286, 15317–15331 (2011).Article
CAS
PubMed
PubMed Central
Google Scholar
Rauch, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381–385 (2020).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar
Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).Article
CAS
PubMed
PubMed Central
Google Scholar
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).Article
CAS
PubMed
Google Scholar
Tarutani, A. et al. Human tauopathy-derived tau strains determine the substrates recruited for templated amplification. Brain 144, 2333–2348 (2021).Article
PubMed
PubMed Central
Google Scholar
Tarutani, A., Arai, T., Murayama, S., Hisanaga, S.-I. & Hasegawa, M. Potent prion-like behaviors of pathogenic α-synuclein and evaluation of inactivation methods. Acta Neuropathol. Commun. 6, 29 (2018).Article
PubMed
PubMed Central
Google Scholar
Taniguchi-Watanabe, S. et al. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol. 131, 267–280 (2016).Article
CAS
PubMed
Google Scholar
He, S. & Scheres, S. H. W. Helical reconstruction in RELION. J. Struct. Biol. 198, 163–176 (2017).Article
CAS
PubMed
Google Scholar
Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).Article
PubMed
PubMed Central
Google Scholar
Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).Article
PubMed
PubMed Central
Google Scholar
Lövestam, S., Shi, J., Li, D., Jamali, K. & Scheres, S. H. W. Cryo-EM image processing of amyloid filaments in RELION-5.1. 2026.03.17.712386. Preprint at bioRxiv https://doi.org/10.64898/2026.03.17.712386 (2026).Zivanov, J., Nakane, T. & Scheres, S. H. W. A Bayesian approach to beam-induced motion correction in cryo-EM single-particle analysis. IUCrJ 6, 5–17 (2019).Article
CAS
PubMed
PubMed Central
Google Scholar
Zivanov, J., Nakane, T. & Scheres, S. H. W. Estimation of high-order aberrations and anisotropic magnification from cryo-EM data sets in RELION-3.1. IUCrJ 7, 253–267 (2020).Article
CAS
PubMed
PubMed Central
Google Scholar
Scheres, S. H. W. & Chen, S. Prevention of overfitting in cryo-EM structure determination. Nat. Methods 9, 853–854 (2012).Article
CAS
PubMed
PubMed Central
Google Scholar
Croll, T. I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D Struct. Biol. 74, 519–530 (2018).Article
ADS
CAS
PubMed
PubMed Central
Google Scholar