Cryo-EM Structures of Tau Filaments from Alzheimer's Disease

Overview

Journal Nature

Specialty Science

Date 2017 Jul 6

PMID 28678775

Citations 909

Authors

Anthony W P Fitzpatrick

Benjamin Falcon

Shaoda He

Alexey G Murzin

Garib Murshudov

Holly J Garringer

R Anthony Crowther

Bernardino Ghetti

Michel Goedert

Sjors H W Scheres

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies.

Morderer D, Wren M, Liu F, Kouri N, Maistrenko A, Khalil B Mol Neurodegener. 2025; 20(1):32.

PMID: 40082954 PMC: 11905455. DOI: 10.1186/s13024-025-00817-0.

Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W.

Qi C, Lovestam S, Murzin A, Peak-Chew S, Franco C, Bogdani M Nat Struct Mol Biol. 2025; .

PMID: 40044789 DOI: 10.1038/s41594-025-01498-5.

Limitations and Applications of Rodent Models in Tauopathy and Synucleinopathy Research.

Szegvari E, Holec S, Woerman A J Neurochem. 2025; 169(3):e70021.

PMID: 40026260 PMC: 11874209. DOI: 10.1111/jnc.70021.

Advancing Alzheimer's Therapy: Computational strategies and treatment innovations.

Paul J, Malik A, Azmal M, Gulzar T, Afghan M, Talukder O IBRO Neurosci Rep. 2025; 18:270-282.

PMID: 39995567 PMC: 11849200. DOI: 10.1016/j.ibneur.2025.02.002.

Quantitative chemoproteomics reveals dopamine's protective modification of Tau.

Wang Q, Liu Z, Wang Y, Liu Y, Chen Y, Zhang S Nat Chem Biol. 2025; .

PMID: 39979588 DOI: 10.1038/s41589-025-01849-9.

References

Jakes R, Novak M, Davison M, Wischik C . Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer's disease. EMBO J. 1991; 10(10):2725-9. PMC: 452980. DOI: 10.1002/j.1460-2075.1991.tb07820.x. View

Wasmer C, Lange A, Van Melckebeke H, Siemer A, Riek R, Meier B . Amyloid fibrils of the HET-s(218-289) prion form a beta solenoid with a triangular hydrophobic core. Science. 2008; 319(5869):1523-6. DOI: 10.1126/science.1151839. View

Jicha G, Bowser R, Kazam I, Davies P . Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res. 1997; 48(2):128-32. DOI: 10.1002/(sici)1097-4547(19970415)48:2<128::aid-jnr5>3.0.co;2-e. View

He S, Scheres S . Helical reconstruction in RELION. J Struct Biol. 2017; 198(3):163-176. PMC: 5479445. DOI: 10.1016/j.jsb.2017.02.003. View

Poorkaj P, Muma N, Zhukareva V, Cochran E, Shannon K, Hurtig H . An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol. 2002; 52(4):511-6. DOI: 10.1002/ana.10340. View

Goedert M, Spillantini M, Jakes R, Rutherford D, Crowther R . Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989; 3(4):519-26. DOI: 10.1016/0896-6273(89)90210-9. View

Falcon B, Cavallini A, Angers R, Glover S, Murray T, Barnham L . Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem. 2014; 290(2):1049-65. PMC: 4294473. DOI: 10.1074/jbc.M114.589309. View

Kidd M . Paired helical filaments in electron microscopy of Alzheimer's disease. Nature. 1963; 197:192-3. DOI: 10.1038/197192b0. View

Kaufman S, Sanders D, Thomas T, Ruchinskas A, Vaquer-Alicea J, Sharma A . Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron. 2016; 92(4):796-812. PMC: 5392364. DOI: 10.1016/j.neuron.2016.09.055. View

10.

Guo J, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B . Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice. J Exp Med. 2016; 213(12):2635-2654. PMC: 5110027. DOI: 10.1084/jem.20160833. View

11.

Colvin M, Silvers R, Ni Q, Can T, Sergeyev I, Rosay M . Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils. J Am Chem Soc. 2016; 138(30):9663-74. PMC: 5389415. DOI: 10.1021/jacs.6b05129. View

12.

Zhang K . Gctf: Real-time CTF determination and correction. J Struct Biol. 2015; 193(1):1-12. PMC: 4711343. DOI: 10.1016/j.jsb.2015.11.003. View

13.

Jackson S, Kerridge C, Cooper J, Cavallini A, Falcon B, Cella C . Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau. J Neurosci. 2016; 36(3):762-72. PMC: 4719013. DOI: 10.1523/JNEUROSCI.3542-15.2016. View

14.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

15.

Clavaguera F, Akatsu H, Fraser G, Crowther R, Frank S, Hench J . Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013; 110(23):9535-40. PMC: 3677441. DOI: 10.1073/pnas.1301175110. View

16.

Bibow S, Mukrasch M, Chinnathambi S, Biernat J, Griesinger C, Mandelkow E . The dynamic structure of filamentous tau. Angew Chem Int Ed Engl. 2011; 50(48):11520-4. DOI: 10.1002/anie.201105493. View

17.

Murshudov G, Vagin A, Dodson E . Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997; 53(Pt 3):240-55. DOI: 10.1107/S0907444996012255. View

18.

Sawaya M, Sambashivan S, Nelson R, Ivanova M, Sievers S, Apostol M . Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature. 2007; 447(7143):453-7. DOI: 10.1038/nature05695. View

19.

Govaerts C, Wille H, Prusiner S, Cohen F . Evidence for assembly of prions with left-handed beta-helices into trimers. Proc Natl Acad Sci U S A. 2004; 101(22):8342-7. PMC: 420396. DOI: 10.1073/pnas.0402254101. View

20.

Wilcock G, Esiri M . Plaques, tangles and dementia. A quantitative study. J Neurol Sci. 1982; 56(2-3):343-56. DOI: 10.1016/0022-510x(82)90155-1. View