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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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BackgroundFibrilar Polymorphism of the Bacterial Extracellular Matrix Protein TasA
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Polyphenol‐solubility alters amyloid fibril formation of α‐synuclein
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“Thus, paired helical filaments and straight filaments are typically found in AD and they are present inside neurons as neurofibrillary tangles [9] (Table 1).”
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Brain structure and structural basis of neurodegenerative diseases
Yang, J., Sui, S., & Liu, Z. (2022) · Biophysics Reports · doi:10.52601/bpr.2022.220013 · Cited by 20
Velander, P., Wu, L., Hildreth, S. B., Vogelaar, N. J., Mukhopadhyay, B., Helm, R. F., Zhang, S., & Xu, B. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2022.106409 · Cited by 22
Targeting amyloid proteins for clinical diagnosis of neurodegenerative diseases
Zhang, S., Dong, H., Bian, J., Li, D., & Liu, C. (2022) · Fundamental Research · doi:10.1016/j.fmre.2022.10.009 · Cited by 23
Neuroimaging studies of acupuncture on Alzheimer’s disease: a systematic review
Yin, Z., Wang, Z., Li, Y., Zhou, J., Chen, Z., Xia, M., Zhang, X., Wu, J., Zhao, L., & Liang, F. (2023) · BMC Complementary Medicine and Therapies · doi:10.1186/s12906-023-03888-y · Cited by 20
Mondal, R., Sandhu, Y. K., Kamalia, V. M., Delaney, B. A., Syed, A. U., Nguyen, G. A. H., Moran, T. R., Limpengco, R. R., Liang, C., & Mukherjee, J. (2023) · Biomedicines · doi:10.3390/biomedicines11041033 · Cited by 21
“Blind docking of IPPI was performed at four different binding sites, as previously reported [9,26].”
MethodWang, R., Lu, K. P., & Zhou, X. Z. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15909 · Cited by 20
In Situ Observation of Amyloid Nucleation and Fibrillation by FastScan Atomic Force Microscopy
Huang, Q., Wang, H., Gao, H., Cheng, P., Zhu, L., Wang, C., & Yang, Y. (2018) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.8b03143 · Cited by 20
Early mechanisms of amyloid fibril nucleation in model and disease-related proteins
Morel, B., & Conejero‐Lara, F. (2019) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2019.140264 · Cited by 19
Structure of NFT: Biochemical Approach
Hasegawa, M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_2 · Cited by 22
Kolen, K. V., Malia, T., Theunis, C., Nanjunda, R. K., Teplyakov, A., Ernst, R., Wu, S., Luo, J., Borgers, M., Vandermeeren, M., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200544 · Cited by 21
Key Physicochemical and Biological Factors of the Phase Behavior of Tau
Nam, G., Lin, Y., Lim, M. H., & Lee, Y. (2020) · Chem · doi:10.1016/j.chempr.2020.09.012 · Cited by 20
Tau Is Truncated in Five Regions of the Normal Adult Human Brain
Friedrich, M. G., Skora, A. S., Hancock, S. E., Mitchell, T. W., Else, P. L., & Truscott, R. J. W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073521 · Cited by 21
Kroth, H., Oden, F., Molette, J., Schieferstein, H., Gabellieri, E., Mueller, A., Berndt, M., Sreenivasachary, N., Serra, A. M., Capotosti, F., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00861 · Cited by 20
Human chaperones untangle fibrils of the Alzheimer protein TauPreprint
Ferrari, L., Geerts, W. J. C., van Wezel, M. D., Kos, R., Konstantoulea, A., van Bezouwen, L. S., Förster, F. G., & Rüdiger, S. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/426650 · Cited by 19
Post-Translational Modifications Control Phase Transitions of Tau
Powell, W. C., Nahum, M., Pankratz, K., Herlory, M., Greenwood, J., Poliyenko, D., Holland, P., Jing, R., Biggerstaff, L., Stowell, M. H. B., et al. (2024) · ACS Central Science · doi:10.1021/acscentsci.4c01319 · Cited by 24
Didonna, A., Cantó, E., Shams, H., Isobe, N., Zhao, C., Caillier, S. J., Condello, C., Yamate-Morgan, H., Tiwari-Woodruff, S. K., Mofrad, M. R. K., et al. (2019) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.04.003 · Cited by 19
“The structure of human Tau fragment including residue K317 was obtained from isolating one chain from amyloid filaments extracted from AD brain (PDB ID: 5O3T) [26].”
BackgroundMethodRecombinant production and purification of the human protein Tau
Ferrari, L., & Rüdiger, S. (2018) · Protein Engineering Design and Selection · doi:10.1093/protein/gzz010 · Cited by 17
Kuo, Y., Lou, Y.-I., Rajesh, R., & Chen, C.-L. (2020) · Journal of the Taiwan Institute of Chemical Engineers · doi:10.1016/j.jtice.2020.02.017 · Cited by 19
Asparagine residue 368 is involved in Alzheimer's disease tau strain–specific aggregation
Shimonaka, S., Matsumoto, S., Elahi, M., Ishiguro, K., Hasegawa, M., Hattori, N., & Motoi, Y. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013271 · Cited by 18
Atomic Force Microscopy Imaging and Nanomechanical Properties of Six Tau Isoform Assemblies
Makky, A., Bousset, L., Madiona, K., & Melki, R. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2020.10.045 · Cited by 19
Identification of cis-acting determinants mediating the unconventional secretion of tau
Katsinelos, T., McEwan, W. A., Jahn, T. R., & Nickel, W. (2021) · Scientific Reports · doi:10.1038/s41598-021-92433-3 · Cited by 16
Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98
Diez, L., Kapinos, L. E., Hochmair, J., Hübschmann, S., Dominguez‐Baquero, A., Vogt, A., Rankovic, M., Zweckstetter, M., Lim, R. Y. H., & Wegmann, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073495 · Cited by 20
Mical modulates Tau toxicity via cysteine oxidation in vivo
Prifti, E., Tsakiri, E. N., Vourkou, E., Stamatakis, G. M., Samiotaki, M. K., Skoulakis, E. M. C., & Papanikolopoulou, K. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01348-1 · Cited by 21
“Interestingly, cryo-EM studies of Tau filaments from human patients revealed that the two cysteine residues are not structurally equivalent since Cys322 is incorporated into the core of the fibril whereas Cys291 is disordered and located in the fuzzy-coat [77].”
BackgroundHelboe, L., Rosenqvist, N., Volbracht, C., Pedersen, L. Ø., Pedersen, J. T., Christensen, S., Egebjerg, J., Christoffersen, C. T., Bang‐Andersen, B., Beach, T. G., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220125 · Cited by 20
Tau acetylation at K280 regulates tau phosphorylation
Kim, M.-S., Mun, Y., Lee, S., Cho, W.-Y., Han, S.-H., Kim, D., & Yoon, S. (2022) · International Journal of Neuroscience · doi:10.1080/00207454.2022.2081165 · Cited by 19
Zheng, R., Yan, Y., Pu, J., & Zhang, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169088 · Cited by 19
“Given the formation of fibrils composed of neuronal Hb in diverse neurodegenerative diseases and the involvement of neuronal Hb in disease progression, it is possible to identify a common fibrillization pathway and a widespread structural target via advanced cryo-EM techniques, which have allowed scientists to determi…”
BackgroundHromádková, L., Siddiqi, M. K., Liu, H., & Safar, J. (2022) · Cells · doi:10.3390/cells11192997 · Cited by 19
“Cumulatively, the data imply (i) the existence of separate pathways for PHF and SFs, and (ii) large pools of misfolded tau with nonfibrillar morphology of the aggregates observed in ultracentrifugation sedimentation velocity experiments [10].”
BackgroundInfluentialSolid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391)
Al‐Hilaly, Y. K., Hurt, C., Rickard, J. E., Harrington, C. R., Storey, J. M. D., Wischik, C. M., Serpell, L. C., & Siemer, A. B. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.988074 · Cited by 19
“Furthermore, tau(297391) overlaps with the core of filaments resolved from ex vivo filaments by cryo-EM (Fitzpatrick et al., 2017), was shown to form PHF that resemble those observed in AD patients (AlHilaly et al.”
BackgroundResultJiang, L., Chakraborty, P., Zhang, L., Wong, M., Hill, S. E., Webber, C. J., Libera, J., Blair, L. J., Wolozin, B. L., & Zweckstetter, M. (2023) · Science Advances · doi:10.1126/sciadv.add9789 · Cited by 19
Hindley, N., Avila, A. S., & Henstridge, C. M. (2023) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2023.1130198 · Cited by 20
“For example, it has been used to study the ultrastructure of tau filaments from the brain of an AD patient, revealing how different isoforms of tau aggregate (Fitzpatrick et al., 2017).”
Method
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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