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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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Photo-oxygenation inhibits tau amyloid formation
Suzuki, T., Hori, Y., Sawazaki, T., Shimizu, Y., Nemoto, Y., Taniguchi, A., Ozawa, S., Sohma, Y., Kanai, M., & Tomita, T. (2019) · Chemical Communications · doi:10.1039/c9cc01728c · Cited by 39
Pires, G., McElligott, S., Drusinsky, S., Halliday, G. M., Potier, M., Wısnıewskı, T., & Drummond, E. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0848-6 · Cited by 41
Munari, F., Barracchia, C. G., Franchin, C., Parolini, F., Capaldi, S., Romeo, A., Bubacco, L., Assfalg, M., Arrigoni, G., & D’Onofrio, M. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.201916756 · Cited by 39
Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake
La‐Rocque, S. D., Moretto, E., Butnaru, I., & Schiavo, G. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15144 · Cited by 46
“…different tauopathies (Arakhamia et al., 2020; Falcon, Zhang, Murzin, et al., 2018; Falcon, Zhang, Schweighauser, et al., 2018; Falcon et al., 2019; Fitzpatrick et al., 2017) and thus may follow distinct pathways of internalisation, as demonstrated by the finding that in cultured neurons, HSPGs…”
BackgroundCHIP-mediated hyperubiquitylation of tau promotes its self-assembly into the insoluble tau filaments
Kim, J. H., Lee, J., Choi, W. H., Park, S., Park, S. H., Lee, J. H., Lim, S. M., Mun, J. Y., Cho, H., Han, D., et al. (2021) · Chemical Science · doi:10.1039/d1sc00586c · Cited by 37
CheSPI: chemical shift secondary structure population inference
Nielsen, J. T., & Mulder, F. A. A. (2021) · Journal of Biomolecular NMR · doi:10.1007/s10858-021-00374-w · Cited by 37
Galaz-Montoya, J. G., Shahmoradian, S. H., Shen, K., Frydman, J., & Chiu, W. (2021) · Communications Biology · doi:10.1038/s42003-021-02360-2 · Cited by 39
Malhis, M., Kaniyappan, S., Aillaud, I., Chandupatla, R., Ramirez, L. M., Zweckstetter, M., Horn, A. H. C., Mandelkow�, E., Sticht, H., & Funke, S. A. (2021) · ChemBioChem · doi:10.1002/cbic.202100287 · Cited by 39
The Proteome Folding Problem and Cellular Proteostasis
Powers, E. T., & Gierasch, L. M. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167197 · Cited by 42
Supramolecular assembly of protein building blocks: from folding to function
Kim, N. H., Choi, H., Shahzad, Z. M., Ki, H., Lee, J., Chae, H., & Kim, Y. H. (2022) · Nano Convergence · doi:10.1186/s40580-021-00294-3 · Cited by 42
“There are many different protein units that form amyloid structures, such as β-amyloid peptide(Aβ) [29, 46], α-synuclein [47], and tau protein [48].”
BackgroundBashir, S., Aiman, A., Chaudhary, A. A., Khan, N., Ahanger, I. A., Sami, N., Almugri, E. A., Ali, M. A. M., Khan, S.-U.-D., Shahid, M., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e27949 · Cited by 38
The role of shear forces in primary and secondary nucleation of amyloid fibrils
Axell, E., Hu, J., Lindberg, M., Dear, A. J., Ortigosa-Pascual, L., Andrzejewska, E. A., Šneiderienė, G., Thacker, D., Knowles, T. P. J., Sparr, E., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2322572121 · Cited by 38
Attempt to Untangle the Prion-Like Misfolding Mechanism for Neurodegenerative Diseases
Sarnataro, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103081 · Cited by 39
“Concerning S320F tau, cryo-electron microscopy studies indicate that the mutation would strongly stabilize tau amyloid fibrils fold and subsequent fibril polymerization [65].”
BackgroundBiomolecular condensation of the microtubule-associated protein tau
Ukmar, T., Wegmann, S., & Zweckstetter, M. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.06.007 · Cited by 41
“b structure within the core of insoluble tau deposits [88, 89].”
BackgroundZou, Y. F., Qian, Z., Gong, Y., Tang, Y., Wei, G., & Zhang, Q. (2019) · Physical Chemistry Chemical Physics · doi:10.1039/c9cp04610k · Cited by 38
Retromer regulates the lysosomal clearance of MAPT/tau
Carosi, J. M., Hein, L. K., van den Hurk, M., Adams, R., Milky, B., Singh, S., Bardy, C., Denton, D., Kumar, S., & Sargeant, T. J. (2020) · Autophagy · doi:10.1080/15548627.2020.1821545 · Cited by 41
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Human tauopathy-derived tau strains determine the substrates recruited for templated amplification
Tarutani, A., Miyata, H., Nonaka, T., Hasegawa, K., Yoshida, M., Saito, Y., Murayama, S., Robinson, A., Mann, D. M. A., Tomita, T., et al. (2021) · Brain · doi:10.1093/brain/awab091 · Cited by 37
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“However, despite the recent remarkable progress in high-resolution structural studies of Aβ amyloid fibrils and tau filaments by ssNMR (22, 58, 59) and cryo-EM (60, 61), the relationship between”
BackgroundPrion strains viewed through the lens of cryo-EM
Manka, S. W., Wenborn, A., Collinge, J., & Wadsworth, J. D. F. (2022) · Cell and Tissue Research · doi:10.1007/s00441-022-03676-z · Cited by 39
Ghosh, U., Yau, W., Collinge, J., & Tycko, R. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111863118 · Cited by 38
New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease
Penke, B., Szűcs, M., & Bogár, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065383 · Cited by 39
“Recently, several cryo-EM studies have revealed the structure and peptide chain conformation of the helical filaments isolated from an AD brain at the atomic level [61].”
BackgroundCryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir
Shi, Y., Ghetti, B. F., Goedert, M., & Scheres, S. H. W. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168025 · Cited by 40
Self-citationLung endothelium, tau, and amyloids in health and disease
Balczon, R., Lin, M. T., Voth, S. B., Nelson, A. R., Schupp, J. C., Wagener, B. M., Pittet, J., & Stevens, T. (2023) · Physiological Reviews · doi:10.1152/physrev.00006.2023 · Cited by 40
Li, D., & Liu, C. (2023) · Structure · doi:10.1016/j.str.2023.08.006 · Cited by 39
Padilla-Godínez, F. J., Vázquez-García, E. R., Trujillo-Villagrán, M. I., Soto-Rojas, L. O., Palomero‐Rivero, M., Hernández-González, O., Pérez-Eugenio, F., Collazo-Navarrete, O., Arias-Carrión, Ó., & Guerra‐Crespo, M. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1570553 · Cited by 42
“For instance, tau fibrils from AD brains (Fitzpatrick et al., 2017; Falcon et al., 2018) and α -syn filaments from MSA and LBD brains display extensive structural variations (Schweighauser et al., 2020).”
Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation
Novák, P., Cehlár, O., Škrabana, R., & Novák, M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179942 · Cited by 38
Imaging Protein Misfolding in the Brain Using β-Sheet Ligands
Harada, R., Okamura, N., Furumoto, S., & Yanai, K. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00585 · Cited by 41
“However, a recent study using a novel single particle cryo-EM approach revealed the detailed structure of native tau filaments from an AD brain (Fitzpatrick et al., 2017).”
BackgroundTau exhibits unique seeding properties in globular glial tauopathy
Chung, D. C., Carlomagno, Y., Cook, C. N., Jansen‐West, K. R., Daughrity, L. M., Lewis‐Tuffin, L. J., Castanedes‐Casey, M., Deture, M. A., Dickson, D. W., & Petrucelli, L. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0691-9 · Cited by 38
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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