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Cryo-EM structures of tau filaments from Alzheimer’s disease
Open accessAbstract
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
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“ultra-structural analyses of tau filaments in brains from individuals with AD have shown that tau tangles contain both 3-repeat (3R)-tau and 4-repeat (4R)-tau isoforms (18)”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [18]
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“In AD, tau tangles contain a mixture of 3R- and 4R-tau isoforms to adopt an AD-characteristic topology (18, 19).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [18]
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“In AD, tau filaments assume a cross-β/β-helical fold (10).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [10]
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“Misfolding and aberrant accumulation of Tau is a pathological hallmark of Alzheimer’s disease (AD)18, 19.”
From Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau (2017) · cites this paper as [19]
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“structure of 3repeat tau fibrils from a patient with Pick's disease has recently been determined [47] and differs from the structure of the fibrils from an AD patient [48] supporting the concept that different prion strains have different fibrillar structure and hence would be ex-”
ResultLaos, V., Do, T. D., Bishop, D., Jin, Y., Marsh, N. M., Quon, B., Fetters, M., Cantrell, K. L., Buratto, S. K., & Bowers, M. T. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00337 · Cited by 25
Bhattacharya, S., Xu, L., & Thompson, D. (2018) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.1359 · Cited by 22
“…β -sheet structural motif with in-register parallel-β -sheets as demonstrated by solid-state nuclear magnetic resonance (ssNMR), and more recently by cryo-electron microscopy (cryo-EM) (Figure 2) (Colvin et al., 2016; A. W. P. Fitzpatrick et al., 2017; Tuttle et al., 2016; Walti et al., 2016).”
BackgroundMethodCerebrospinal fluid from Alzheimer’s disease patients promotes tau aggregation in transgenic mice
Skachokova, Z. K., Martinisi, A., Flach, M., Sprenger, F., Naegelin, Y., Steiner-Monard, V., Sollberger, M. A., Monsch, A. U., Goedert, M., Tolnay, M., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0725-3 · Cited by 27
Self-citationBrainbank Neuro-CEB Neuropathology Network, Thierry, M., Boluda, S., Delatour, B., Marty, S., Seilhean, D., Potier, M., & Duyckaerts, C. J. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02108-7 · Cited by 26
Sun, Y., Ma, L., Cai, W., & Shao, X. (2020) · Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy · doi:10.1016/j.saa.2020.118046 · Cited by 24
Sulatsky, M., Sulatskaya, A. I., Stepanenko, O., Povarova, O., Kuznetsova, I. M., & Turoverov, K. (2020) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2020.01.290 · Cited by 22
Tau Interacting Proteins: Gaining Insight into the Roles of Tau in Health and Disease
Stancu, I., Ferraiolo, M., Terwel, D., & Dewachter, I. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_13 · Cited by 23
Weismiller, H. A., Holub, T. J., Krzesinski, B. J., & Margittai, M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101021 · Cited by 24
Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils
Zhou, Y., Li, J., Nordberg, A. K., & Ågren, H. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.1c00536 · Cited by 24
Seed amplification and RT-QuIC assays to investigate protein seed structures and strains
Standke, H. G., & Kraus, A. (2022) · Cell and Tissue Research · doi:10.1007/s00441-022-03595-z · Cited by 26
Künze, G., Kümpfel, R., Rullmann, M., Barthel, H., Brendel, M., Patt, M., & Sabri, O. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00291 · Cited by 22
Cyclic dipeptide‐based small molecules modulate zinc‐mediated liquid–liquid phase separation of tau
Ramesh, M., Balachandra, C., Baruah, P., & Govindaraju, T. (2022) · Journal of Peptide Science · doi:10.1002/psc.3465 · Cited by 25
Morphology-Dependent Interactions between α-Synuclein Monomers and Fibrils
Pálmadóttir, T., Waudby, C. A., Bernfur, K., Christodoulou, J., Linse, S. S., & Malmendal, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065191 · Cited by 22
Hoq, M. R., Bharath, S. R., Hallinan, G. I., Fernández, A., Vago, F. S., Ozcan, K. A., Li, D., Garringer, H. J., Vidal, R., Ghetti, B. F., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02563-3 · Cited by 24
Self-citationDnaJC7 specifically regulates tau seeding
Perez, V. A., Sanders, D. W., Mendoza‐Oliva, A., Stopschinski, B. E., Mullapudi, V., White, C. L., Joachimiak, Ł. A., & Diamond, M. I. (2023) · eLife · doi:10.7554/elife.86936 · Cited by 24
Milligram-scale assembly and NMR fingerprint of tau fibrils adopting the Alzheimer’s disease fold
Duan, P., Mammeri, N. E., & Hong, M. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107326 · Cited by 31
Quo Vadis Biomolecular NMR Spectroscopy?
Selenko, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061278 · Cited by 24
Wu, Y., Lou, L., & Xie, Z. (2020) · Frontiers in Chemistry · doi:10.3389/fchem.2020.00081 · Cited by 24
“Its applicability can be potentially extended beyond the characterizing of SK2 ion channels to investigating other proteins with unknown structures, such as the Alzheimer’s disease related proteins (Fitzpatrick et al., 2017; Hatami et al., 2017), which are also treatment targets of neural degenerative diseases.”
BackgroundRaimondi, S., Mangione, P. P., Verona, G., Canetti, D., Nocerino, P., Marchese, L., Piccarducci, R., Mondani, V., Faravelli, G., Taylor, G. W., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014026 · Cited by 24
“As thermodynamic stability of fibrils is determined by intermolecular bonds, this information may be complementary to the structural observations on fibrils obtained by solid state NMR (SSNMR) (27) and cryo-EM, which have recently been applied to a number of natural pathologic filaments (28) and fibrils (14,15,29).”
BackgroundKreutzer, A. G., Samdin, T. D., Guaglianone, G., Spencer, R. K., & Nowick, J. S. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00290 · Cited by 25
Ostermeier, L., de Oliveira, G. A. P., Dzwolak, W., Silva, J. L., & Winter, R. (2020) · Biophysical Chemistry · doi:10.1016/j.bpc.2020.106506 · Cited by 24
Inhibition of amyloid formation of the Nucleoprotein of SARS-CoV-2Preprint
Tayeb-Fligelman, E., Cheng, X., Tai, C. E., Bowler, J. T., Griner, S. L., Sawaya, M. R., Seidler, P. M., Jiang, Y. X., Lu, J., Rosenberg, G. M., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.05.434000 · Cited by 25
“(42, 43) ), both homo- and hetero-zippers are seen.”
Yang, H., Yuan, P., Wu, Y., Shi, M., Caro, C. D., Tengeiji, A., Yamanoi, S., Inoue, M., DeGrado, W. F., & Condello, C. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2300769120 · Cited by 19
Ligands for Protein Fibrils of Amyloid-β, α-Synuclein, and Tau
Chisholm, T. S., & Hunter, C. A. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00838 · Cited by 26
Hochmair, J., van den Oetelaar, M. C. M., Ravatt, L. M., Diez, L., Lemmens, L. J. M., Ponce-Lina, R., Sankar, R., Franck, M., Nolte, G., Semenova, E., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-08548-0 · Cited by 26
“Because of the high 14-3-3 abundance in the brain, binding of 14-3-3 to Tau phosphorylated at pS214/pS324 (Tau pS214/pS324 ) could provide a robust mechanism for promoting the solubility of PKA-phosphorylated Tau (PKA-Tau) and preventing its aggregation.”
InfluentialDułak, D., Gadzała, M., Banach, M., Ptak, M., Wiśniowski, Z., Konieczny, L., & Roterman, I. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102910 · Cited by 22
“Fragment: residues 623–695 of tau protein (306–378 according to PDB numbering) Chains A, C, E, G, I, along with their counterparts (B, D, F, H, J) make up the proto-fibrils [11].”
BackgroundInfluentialThe role of annealing and fragmentation in human tau aggregation dynamics
Huseby, C. J., Bundschuh, R. A., & Kuret, J. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006943 · Cited by 23
“” This structure, which has been detected on synthetic 2N4R tau filaments (56) as well as authentic brain-derived filaments (57), arises from the intrinsically disordered regions of tau protomers that extend away from the cross- -sheet aggregate core (58).”
Background
Metadata
- Authors
- Fitzpatrick, A. W. P., Falcon, B., He, S., Murzin, A. G., Murshudov, G., Garringer, H. J., Crowther, R. A., Ghetti, B., Goedert, M., & Scheres, S. H. W.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Indiana University Indianapolis (US)
- Corresponding author
- Goedert, Michel
- Scheres, Sjors H. W.
- ORCID
- Venue
- Nature
- Published
- 2017-07
- Volume
- 547
- Issue
- 7662
- Pages
- 185-190
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5552202
- OpenAlex
- W2727929522
- Cited by
- 2,061
- References
- 58
- Citations by year
- 2026: 197 · 2025: 224 · 2024: 225 · 2023: 224 · 2022: 214 · 2021: 231 · 2020: 280 · 2019: 227 · 2018: 193 · 2017: 42
- FWCI
- 150.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- PMC
- Funders
- Medical Research Council (MC_EX_MR/N027892/1)
- National Institute on Aging (P30AG010133)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, tau filaments, paired helical filaments, straight filaments, tau aggregation, protofilaments, tauopathy, neurodegenerative diseases
- MeSH terms
- Aged, Alzheimer Disease, Amino Acid Sequence, Amyloid, Brain, Female, Humans, tau Proteins, Cryoelectron Microscopy, Protein Aggregation, Pathological
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