Peng, C., Trojanowski, J. Q. & Lee, V. M.-Y. Protein transmission in neurodegenerative disease. Nat. Rev. Neurol. 16, 199–212 (2020).
Collinge, J. & Clarke, A. R. A general model of prion strains and their pathogenicity. Science 318, 930–936 (2007).
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).
Alam, P. et al. Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer. Acta Neuropathol. 148, 56 (2024).
Hoyt, F. et al. Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains. Nat. Commun. 13, 4005 (2022).
Kraus, A. et al. High-resolution structure and strain comparison of infectious mammalian prions. Mol. Cell 81, 4540–4551.e6 (2021).
Manka, S. W. et al. A structural basis for prion strain diversity. Nat. Chem. Biol. 19, 607–613 (2023).
Manka, S. W. et al. 2.7 Å cryo-EM structure of ex vivo RML prion fibrils. Nat. Commun. 13, 4004 (2022).
Goedert, M., Crowther, R. A., Scheres, S. H. W. & Spillantini, M. G. Tau and neurodegeneration. Cytoskeleton 81, 95–102 (2024).
Shi, Y. et al. Structure-based classification of tauopathies. Nature 598, 359–363 (2021).
Scheres, S. H. W., Ryskeldi-Falcon, B. & Goedert, M. Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids. Nature 621, 701–710 (2023).
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).
Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).
Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl Acad. Sci. USA 110, 9535–9540 (2013).
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).
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).
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).
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).
Narasimhan, S. et al. Human tau pathology transmits glial tau aggregates in the absence of neuronal tau. J. Exp. Med. 217, e20190783 (2020).
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).
He, Z. et al. Transmission of tauopathy strains is independent of their isoform composition. Nat. Commun. 11, 7 (2020).
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).
Kasen, A. et al. Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency. Nat. Commun. 16, 9240 (2025).
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).
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).
Burger, D. et al. Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology. Nature 648, 409–417 (2025).
Yoshida, M. Astrocytic inclusions in progressive supranuclear palsy and corticobasal degeneration. Neuropathology 34, 555–570 (2014).
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).
Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).
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).
Zhang, W. et al. Novel tau filament fold in corticobasal degeneration. Nature 580, 283–287 (2020).
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).
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).
Andorfer, C. et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 86, 582–590 (2003).
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).
Banerjee, G. et al. Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone. Nat. Med. 30, 394–402 (2024).
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).
Allen, B. et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351 (2002).
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).
Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405 (2000).
Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).
Darricau, M. et al. Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates. Brain 146, 2524–2534 (2023).
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).
Rauch, J. N. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381–385 (2020).
Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
Tarutani, A. et al. Human tauopathy-derived tau strains determine the substrates recruited for templated amplification. Brain 144, 2333–2348 (2021).
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).
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).
He, S. & Scheres, S. H. W. Helical reconstruction in RELION. J. Struct. Biol. 198, 163–176 (2017).
Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).
Rohou, A. & Grigorieff, N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 192, 216–221 (2015).
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).
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).
Scheres, S. H. W. & Chen, S. Prevention of overfitting in cryo-EM structure determination. Nat. Methods 9, 853–854 (2012).
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).