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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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“A growing body of evidence suggests that misfolded tau tends to be truncated and frequently consists of different conformers or structural polymorphisms, dependent on the stages and disease of tauopathy (Fitzpatrick et al., 2017; Falcon et al., 2018, 2019; Sigurdsson, 2018; Zhang et al., 2020).”
BackgroundMolecular Pathogenesis of the Tauopathies
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Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability
Alonso, A. D., Cohen, L. S., Corbo, C., Morozova, V., ElIdrissi, A., Phillips, G., & Kleiman, F. E. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00338 · Cited by 278
“As an IDP, the secondary structure of tau is not defined, however, tau structural information is very important in the formation of PHF/SF in AD brains (Fitzpatrick et al., 2017).”
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CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
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Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation
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Mechanisms and pathology of protein misfolding and aggregation
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“2), whereas tau forms ultrastructural polymorphs that are classified between different tauopathies and share several different protofilament folds 145–147 . αS forms distinct fibrils in multiple system atrophy (MSA) and Parkinson disease 148,149 .”
BackgroundCryo-EM structures of four polymorphic TDP-43 amyloid cores
Cao, Q., Boyer, D. R., Sawaya, M. R., Ge, P., & Eisenberg, D. S. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0248-4 · Cited by 247
Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy
Cope, T., Rittman, T., Borchert, R. J., Jones, P. S., Vatansever, D., Allinson, K. S. J., Passamonti, L., Rodríguez, P. V., Bevan-Jones, W. R., O'Brien, J. T., et al. (2017) · Brain · doi:10.1093/brain/awx347 · Cited by 251
Inert and seed-competent tau monomers suggest structural origins of aggregation
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Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts
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Cellular and pathological heterogeneity of primary tauopathies
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Enzymatic Noncovalent Synthesis
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Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids
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Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components
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Disease-specific tau filaments assemble via polymorphic intermediates
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“The tau(297–391) construct, upon shaking in phosphate buffer with magnesium chloride, forms PHFs with ordered cores that are identical to those from human brains 3,8 .”
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Tau local structure shields an amyloid-forming motif and controls aggregation propensity
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“To test whether isomerization of P301 could influence spontaneous amyloid formation, we constructed a series of R2R3 peptide fragments with proline analogs that preferentially populate either: (1) a cis rotamer (2S,4S)fluoroproline; (2) a trans rotamer (2S,4R)-fluoroproline; or (3) an analog that easily interconverts…”
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“Protein aggregation is widely considered as inherently pathogenic in neurodegeneration (Fitzpatrick et al., 2017; Hernández-Vega et al., 2017), altering many cellular functions, most notably autophagy and proteostasis (Bence et al.”
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Age-dependent formation of TMEM106B amyloid filaments in human brains
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“The same protein sequences can also lead to disease-specific folds of tau filaments, as in AD and chronic traumatic encephalopathy, in which all 6 tau isoforms are present (8,9).”
BackgroundFrom the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy
Colin, M., Dujardin, S., Schraen-Maschke, S., Meno-Tetang, G., Duyckaerts, C., Courade, J.-P., & Buée, L. (2020) · Acta Neuropathologica · doi:10.1007/s00401-019-02087-9 · Cited by 187
Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue
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Amyloid structures: much more than just a cross-β fold
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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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