Cofactors are essential constituents of stable and seeding-active tau fibrils
Open accessAbstract
Amyloid fibrils are cross-β-rich aggregates that are exceptionally stable forms of protein assembly. Accumulation of tau amyloid fibrils is involved in many neurodegenerative diseases, including Alzheimer's disease (AD). Heparin-induced aggregates have been widely used and assumed to be a good tau amyloid fibril model for most biophysical studies. Here we show that mature fibrils made of 4R tau variants, prepared with heparin or RNA, spontaneously depolymerize and release monomers when their cofactors are removed. We demonstrate that the cross-β-sheet assembly formed in vitro with polyanion addition is unstable at room temperature. We furthermore demonstrate high seeding capacity with transgenic AD mouse brain-extracted tau fibrils in vitro that, however, is exhausted after one generation, while supplementation with RNA cofactors resulted in sustained seeding over multiple generations. We suggest that tau fibrils formed in brains are supported by unknown cofactors and inhere higher-quality packing, as reflected in a more distinct conformational arrangement in the mouse fibril-seeded, compared with heparin-induced, tau fibrils. Our study suggests that the role of cofactors in tauopathies is a worthy focus of future studies, as they may be viable targets for diagnosis and therapeutics.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Anionic experimental cofactor models, including heparin and RNA or its associated granules, promote Tau aggregation.
“anionic experimental cofactor models have been described to promote aggregation: heparin (Goedert et al., 1996; Fichou et al., 2018) and RNA or its associated granules (Kampers et al., 1996; Zhang et al., 2017; Dinkel et al., 2015).”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Fichou et al., 2018
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cryo-EM structures of tau filaments from Alzheimer’s disease
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. (2017) · Nature · doi:10.1038/nature23002 · Cited by 2,061 · cited 3× · see citing works
“However, under pathological conditions, it can assemble into amyloid fibrils in which parts of its microtubule-binding domain, predominantly positively charged, densely pack into a cross-β-sheet arrangement (5).”
BackgroundResultGoedert, M., Jakes, R., Spillantini, M. G., Hasegawa, M., Smith, M. J., & Crowther, R. A. (1996) · Nature · doi:10.1038/383550a0 · Cited by 1,036 · see citing works
Distinct Tau Prion Strains Propagate in Cells and Mice and Define Different Tauopathies
Sanders, D. W., Kaufman, S. K., DeVos, S. L., Sharma, A. M., Mirbaha, H., Li, A., Barker, S. J., Foley, A. C., Thorpe, J. R., Serpell, L. C., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.04.047 · Cited by 986 · see citing works
Biochemistry and Cell Biology of Tau Protein in Neurofibrillary DegenerationPreprint
Mandelkow, E., & Mandelkow, E. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006247 · Cited by 839 · see citing works
Structures of filaments from Pick’s disease reveal a novel tau protein fold
Falcon, B., Zhang, W., Murzin, A. G., Murshudov, G. N., Garringer, H. J., Vidal, R., Crowther, R. A., Ghetti, B. F., Scheres, S. H. W., & Goedert, M. (2018) · Nature · doi:10.1038/s41586-018-0454-y · Cited by 837 · see citing works
Role of Intermolecular Forces in Defining Material Properties of Protein Nanofibrils
Knowles, T. P. J., Fitzpatrick, A. W. P., Meehan, S., Mott, H. R., Vendruscolo, M., Dobson, C. M., & Welland, M. E. (2007) · Science · doi:10.1126/science.1150057 · Cited by 782 · see citing works
Proteopathic tau seeding predicts tauopathy in vivo
Holmes, B. B., Furman, J. L., Mahan, T. E., Yamasaki, T. R., Mirbaha, H., Eades, W. C., Belaygorod, L., Cairns, N. J., Holtzman, D. M., & Diamond, M. I. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411649111 · Cited by 696 · see citing works
Biology of Amyloid: Structure, Function, and Regulation
Greenwald, J., & Riek, R. (2010) · Structure · doi:10.1016/j.str.2010.08.009 · Cited by 573 · see citing works
Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E.-M., & Mandelkow, E. (1996) · FEBS Letters · doi:10.1016/s0014-5793(96)01386-5 · Cited by 548 · see citing works
Kaufman, S. K., Sanders, D. W., Thomas, T. L., Ruchinskas, A. J., Vaquer-Alicea, J., Sharma, A. M., Miller, T. M., & Diamond, M. I. (2016) · Neuron · doi:10.1016/j.neuron.2016.09.055 · Cited by 450 · see citing works
Guo, J. L., Narasimhan, S., Changolkar, L., He, Z., Stieber, A., Zhang, B., Gathagan, R. J., Iba, M., McBride, J. D., Trojanowski, J. Q., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20160833 · Cited by 440 · see citing works
Nuclear Tau, a Key Player in Neuronal DNA Protection
Sultan, A., Nesslany, F., Violet, M., Bégard, S., Loyens, A., Talahari, S., Mansuroglu, Z., Marzin, D., Sergeant, N., Humez, S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.199976 · Cited by 421 · cited 1× · see citing works
“Although tau is mostly present in axons (30), it is also found in neuronal nuclei (31) and is suspected to traffic in the extracellular matrix (32).”
BackgroundInvestigation of structure and dynamics in membrane proteins using site-directed spin labeling
Hubbell, W. L., & Altenbach, C. (1994) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(94)90219-4 · Cited by 396 · see citing works
(1997) · Europe PMC (PubMed Central) · Cited by 354 · see citing works
The Yin and Yang of protein folding
Jahn, T. R., & Radford, S. E. (2005) · FEBS Journal · doi:10.1111/j.1742-4658.2005.05021.x · Cited by 323 · see citing works
RNA stores tau reversibly in complex coacervates
Zhang, X., Lin, Y., Eschmann, N. A., Zhou, H., Rauch, J. N., Hernández, I., Guzman, E., Kosik, K. S., & Han, S. (2017) · PLoS Biology · doi:10.1371/journal.pbio.2002183 · Cited by 308 · see citing works
Conformation Determines the Seeding Potencies of Native and Recombinant Tau Aggregates
Falcon, B., Cavallini, A., Angers, R. C., Glover, S. J., Murray, T. K., Barnham, L., Jackson, S., O'Neill, M. J., Isaacs, A. M., Hutton, M. L., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.589309 · Cited by 252 · see citing works
Inert and seed-competent tau monomers suggest structural origins of aggregation
Mirbaha, H., Chen, D., Morazova, O. A., Ruff, K. M., Sharma, A. M., Liu, X., Goodarzi, M., Pappu, R. V., Colby, D. W., Mirzaei, H., et al. (2018) · eLife · doi:10.7554/elife.36584 · Cited by 225 · see citing works
Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs)
Rauch, J. N., Chen, J. J., Sorum, A. W., Miller, G. M., Sharf, T., See, S. K., Hsieh-Wilson, L. C., Kampmann, M., & Kosik, K. S. (2018) · Scientific Reports · doi:10.1038/s41598-018-24904-z · Cited by 211 · cited 1× · see citing works
“GAG, in particular heparan sulfate (HS), has been the most studied interaction partner to tau [see, for instance, a recent review (33)], likely because (i) it was found colocalized with tau neurofibrillary tangles (NFTs) in AD brain (6), (ii) heparin is a very efficient cofactor in promoting aggregation in vitro (6),…”
BackgroundTau Pathology in a Family with Dementia and a P301L Mutation in Tau
Mirra, S. S., Murrell, J. R., Gearing, M., Spillantini, M. G., Goedert, M., Crowther, R. A., Levey, A. I., Jones, R., Green, J., Shoffner, J. M., et al. (1999) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199904000-00004 · Cited by 191 · see citing works
Structural Impact of Heparin Binding to Full-Length Tau As Studied by NMR Spectroscopy
Sibille, N., Sillen, A., Leroy, A., Wieruszeski, J., Mulloy, B., Landrieu, I., & Lippens, G. M. (2006) · Biochemistry · doi:10.1021/bi060964o · Cited by 175 · see citing works
Woerman, A. L., Aoyagi, A., Patel, S. S., Kazmi, S. A., Lobach, I. V., Grinberg, L. T., McKee, A. C., Seeley, W. W., Olson, S. H., & Prusiner, S. B. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616344113 · Cited by 174 · see citing works
RNA sequestration to pathological lesions of neurodegenerative diseases
Ginsberg, S. D., Galvin, J. E., Chiu, T.-L. S., Lee, V. M. ‐., Masliah, E., & Trojanowski, J. Q. (1998) · Acta Neuropathologica · doi:10.1007/s004010050923 · Cited by 142 · see citing works
von Bergen�, M., Barghorn, S., Müller, S. A., Pickhardt, M., Biernat, J., Mandelkow, E., Davies, P., Aebi, U., & Mandelkow�, E. (2006) · Biochemistry · doi:10.1021/bi052530j · Cited by 141 · see citing works
Ramachandran, G., & Udgaonkar, J. B. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.271874 · Cited by 140 · see citing works
Fichou, Y., Vigers, M., Goring, A. K., Eschmann, N. A., & Han, S. (2018) · Chemical Communications · doi:10.1039/c8cc01355a · Cited by 89 · see citing works
Morozova, O. A., March, Z. M., Robinson, A. S., & Colby, D. W. (2013) · Biochemistry · doi:10.1021/bi400866w · Cited by 87 · see citing works
The role of heparan sulfates in protein aggregation and their potential impact on neurodegeneration
Maïza, A., Chantepie, S., Vera, C., Fifre, A., Huynh, M. B., Stettler, O., Ouidja, M. O., & Papy-García, D. (2018) · FEBS Letters · doi:10.1002/1873-3468.13082 · Cited by 87 · see citing works
RNA Binds to Tau Fibrils and Sustains Template-Assisted Growth
Dinkel, P. D., Holden, M. R., Matin, N., & Margittai, M. (2015) · Biochemistry · doi:10.1021/acs.biochem.5b00453 · Cited by 84 · see citing works
Extracellular Tau and Its Potential Role in the Propagation of Tau Pathology
Yamada, K. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00667 · Cited by 84 · see citing works
Signature of an aggregation-prone conformation of tau
Eschmann, N. A., Georgieva, E. R., Ganguly, P., Borbat, P. P., Rappaport, M. D., Akdoğan, Y., Freed, J. H., Shea, J., & Han, S. (2017) · Scientific Reports · doi:10.1038/srep44739 · Cited by 82 · see citing works
Pavlova, À., Cheng, C., Kinnebrew, M., Lew, J., Dahlquist, F. W., & Han, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1504415113 · Cited by 79 · see citing works
A Complex Mechanism for Inducer Mediated Tau Polymerization
Carlson, S. W., Branden, M., Voss, K., Sun, Q., Rankin, C. A., & Gamblin, T. C. (2007) · Biochemistry · doi:10.1021/bi700403a · Cited by 73 · see citing works
Amplification of Tau Fibrils from Minute Quantities of Seeds
Meyer, V., Dinkel, P. D., Hager, E. R., & Margittai, M. (2014) · Biochemistry · doi:10.1021/bi501050g · Cited by 70 · see citing works
Srivastava, M., Georgieva, E. R., & Freed, J. H. (2017) · The Journal of Physical Chemistry A · doi:10.1021/acs.jpca.7b00183 · Cited by 59 · see citing works
Srivastava, M., & Freed, J. H. (2017) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.7b02379 · Cited by 59 · see citing works
Xia, D., Gutmann, J. M., & Götz, J. (2016) · Scientific Reports · doi:10.1038/srep29074 · Cited by 47 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease
Wesseling, H., Mair, W., Kumar, M., Schlaffner, C. N., Tang, S., Beerepoot, P., Fatou, B., Guise, A. J., Cheng, L., Takeda, S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.029 · Cited by 688 · see citing works
“To overcome these electrostatic forces and promote aggregation, charge neutralization of the MBD is required, and anionic experimental cofactor models have been described to promote aggregation: heparin (Goedert et al., 1996; Fichou et al., 2018) and RNA or its associated granules (Kampers et al.”
BackgroundNguyen, P. H., Ramamoorthy, A., Sahoo, B. R., Zheng, J., Faller, P., Straub, J. E., Domı́nguez, L., Shea, J., Dokholyan, N. V., Simone, A. D., et al. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01122 · Cited by 676 · see citing works
Amyloid-type Protein Aggregation and Prion-like Properties of Amyloids
Willbold, D., Strodel, B., Schroeder, G. F., Hoyer, W., & Heise, H. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00196 · Cited by 222 · see citing works
Amyloid structures: much more than just a cross-β fold
Gallardo, R. U., Ranson, N. A., & Radford, S. E. (2019) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2019.09.001 · Cited by 189 · see citing works
Limorenko, G., & Lashuel, H. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00127b · Cited by 162 · see citing works
The proline-rich domain promotes Tau liquid–liquid phase separation in cells
Zhang, X., Vigers, M. P., McCarty, J., Rauch, J. N., Fredrickson, G. H., Wilson, M. Z., Shea, J., Han, S., & Kosik, K. S. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.202006054 · Cited by 123 · see citing works
Abskharon, R. N. N., Sawaya, M. R., Boyer, D. R., Cao, Q., Nguyen, B. A., Cascio, D., & Eisenberg, D. S. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2119952119 · Cited by 97 · see citing works
Lin, Y., Fichou, Y., Zeng, Z., Hu, N. Y., & Han, S. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00627 · Cited by 92 · see citing works
Liquid–liquid phase separation of Tau by self and complex coacervation
Najafi, S., Lin, Y., Longhini, A. P., Zhang, X., Delaney, K. T., Kosik, K. S., Fredrickson, G. H., Shea, J., & Han, S. (2021) · Protein Science · doi:10.1002/pro.4101 · Cited by 87 · see citing works
Ordered Assembly of Tau Protein and Neurodegeneration
Goedert, M., & Spillantini, M. G. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_1 · Cited by 71 · see citing works
Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43
Tarutani, A., Adachi, T., Akatsu, H., Hashizume, Y., Hasegawa, K., Saito, Y., Robinson, A., Mann, D. M. A., Yoshida, M., Murayama, S., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02426-3 · Cited by 74 · see citing works
Bassoon contributes to tau-seed propagation and neurotoxicity
Martinez, P., Patel, H., You, Y., Jury, N., Perkins, A., Lee-Gosselin, A., Taylor, X., You, Y., Viana Di Prisco, G., Huang, X., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01191-6 · Cited by 68 · see citing works
The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges
Zheng, H., Sun, H., Cai, Q., & Tai, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094969 · Cited by 65 · see citing works
Fichou, Y., Al‐Hilaly, Y. K., Devred, F., Smet‐Nocca, C., Tsvetkov, P. O., Verelst, J., Winderickx, J., Geukens, N., Vanmechelen, E., Perrotin, A., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0682-x · Cited by 63 · see citing works
Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target
Oakley, S. S., Maina, M. B., Marshall, K. E., Al‐Hilaly, Y. K., Harrington, C., Wischik, C. M., & Serpell, L. C. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.590754 · Cited by 57 · see citing works
Cantrelle, F., Loyens, A., Trivelli, X., Reimann, O., Despres, C., Gandhi, N. S., Hackenberger, C. P. R., Landrieu, I., & Smet‐Nocca, C. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.661368 · Cited by 61 · see citing works
Despres, C., Di, J., Cantrelle, F., Li, Z., Huvent, I., Chambraud, B., Zhao, J., Chen, J., Chen, S., Lippens, G. M., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00325 · Cited by 59 · see citing works
Lipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein
Majewski, J. P., Jones, E. M., Zanden, C. M. V., Biernat, J., Mandelkow�, E., & Chi, E. Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-70208-6 · Cited by 56 · see citing works
Tau-Cofactor Complexes as Building Blocks of Tau Fibrils
Fichou, Y., Oberholtzer, Z. R., Ngo, H., Cheng, C., Keller, T. J., Eschmann, N. A., & Han, S. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01339 · Cited by 57 · see citing works
van der Kant, R., Louros, N. N., Schymkowitz, J. W. H., & Rousseau, F. (2022) · Structure · doi:10.1016/j.str.2022.05.002 · Cited by 54 · see citing works
Mamsa, S. S. A., & Meloni, B. P. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.759729 · Cited by 50 · see citing works
Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States
Montgomery, K. M., Carroll, E. C., Thwin, A. C., Quddus, A., Hodges, P., Southworth, D. R., & Gestwicki, J. E. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c08004 · Cited by 49 · see citing works
In vitro amplification of pathogenic tau conserves disease-specific bioactive characteristics
Xu, H. W., O’Reilly, M., Gibbons, G. S., Changolkar, L. N., McBride, J. D., Riddle, D. M., Zhang, B., Stieber, A., Nirschl, J., Kim, S., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-020-02253-4 · Cited by 49 · see citing works
Mah, D., Zhao, J., Liu, X., Zhang, F., Liu, J., Wang, L., Linhardt, R. J., & Wang, C. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.671458 · Cited by 44 · see citing works
RNA induces unique tau strains and stabilizes Alzheimer’s disease seeds
Zwierzchowski-Zarate, A. N., Mendoza‐Oliva, A., Kashmer, O. M., Collazo-Lopez, J. E., White, C. L., & Diamond, M. I. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102132 · Cited by 45 · see citing works
Mechanisms of Heparin-Induced Tau Aggregation Revealed by a Single Nanopore
Giamblanco, N., Fichou, Y., Janot, J., Balanzat, E., Han, S., & Balme, S. (2020) · ACS Sensors · doi:10.1021/acssensors.0c00193 · Cited by 43 · see citing works
Assembly of transgenic human P301S Tau is necessary for neurodegeneration in murine spinal cord
Macdonald, J. A., Bronner, I. F., Drynan, L. F., Fan, J., Curry, A., Fraser, G. M., Lavenir, I., & Goedert, M. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0695-5 · Cited by 38 · see citing works
To target Tau pathologies, we must embrace and reconstruct their complexities
Limorenko, G., & Lashuel, H. A. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105536 · Cited by 39 · see citing works
Conformational fingerprinting of tau variants and strains by Raman spectroscopy
Devitt, G., Crisford, A., Rice, W., Weismiller, H. A., Fan, Z., Commins, C., Hyman, B. T., Margittai, M., Mahajan, S., & Mudher, A. K. (2021) · RSC Advances · doi:10.1039/d1ra00870f · Cited by 37 · see citing works
Tau proteinopathies and the prion concept
(2020) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2020.08.003 · Cited by 38 · see citing works
Structures of Pathological and Functional Amyloids and Prions, a Solid-State NMR Perspective
Daskalov, A., Mammeri, N. E., Lends, A., Shenoy, J., Lamon, G., Fichou, Y., Saad, A., Martinez, D., Morvan, E., Berbon, M., et al. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.670513 · Cited by 33 · see citing works
Tau Protein and Frontotemporal Dementias
Goedert, M., Spillantini, M. G., Falcon, B., Zhang, W., Newell, K. L., Hasegawa, M., Scheres, S. H. W., & Ghetti, B. F. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-51140-1_12 · Cited by 33 · see citing works
Biophysical properties of a tau seed
Hou, Z., Chen, D., Ryder, B. D., & Joachimiak, Ł. A. (2021) · Scientific Reports · doi:10.1038/s41598-021-93093-z · Cited by 31 · see citing works
Townsend, D. J., Fullwood, N. J., Yates, E. A., & Middleton, D. A. (2020) · Biochemistry · doi:10.1021/acs.biochem.0c00443 · Cited by 32 · see citing works
Chemical Synthesis Reveals Pathogenic Role of N-Glycosylation in Microtubule-Associated Protein Tau
Powell, W. C., Jing, R., Herlory, M., Holland, P., Poliyenko, D., Ebmeier, C. C., Stowell, M. H. B., & Walczak, M. A. A. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c17873 · Cited by 32 · see citing works
Protein Amyloid Cofactors: Charged Side-Chain Arrays Meet Their Match?
Lewkowicz, E., Jayaraman, S., & Gursky, O. (2021) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2021.05.003 · Cited by 32 · see citing works
Mutations in Tau Protein Promote Aggregation by Favoring Extended Conformations
Pounot, K., Piersson, C., Goring, A. K., Rosu, F., Gabelica, V., Weik, M., Han, S., & Fichou, Y. (2023) · JACS Au · doi:10.1021/jacsau.3c00550 · Cited by 31 · see citing works
Banerjee, S., Ferdosh, S., Ghosh, A. N., & Barat, C. (2020) · Scientific Reports · doi:10.1038/s41598-020-61777-7 · Cited by 31 · see citing works
Kang, S., Han, Z. Z., Daude, N., McNamara, E., Wohlgemuth, S. L., Molina‐Porcel, L., Safar, J., Mok, S., & Westaway, D. A. (2021) · BMC Biology · doi:10.1186/s12915-021-01132-y · Cited by 31 · see citing works
Alzheimer’s disease seeded tau forms paired helical filaments yet lacks seeding potential
Duan, P., Dregni, A. J., Xu, H. W., Changolkar, L. N., Lee, V. M. ‐., Lee, E. B., & Hong, M. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107730 · Cited by 35 · see citing works
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 23 · see citing works
Heparan Sulfate Proteoglycans in Tauopathy
Zhu, Y., Gandy, L. A., Zhang, F., Liu, J., Wang, C., Blair, L. J., Linhardt, R. J., & Wang, L. (2022) · Biomolecules · doi:10.3390/biom12121792 · Cited by 23 · see citing works
Identifying Protein Conformational Dynamics Using Spin‐label ESR
Lai, Y., Kuo, Y., & Chiang, Y. (2019) · Chemistry - An Asian Journal · doi:10.1002/asia.201900855 · Cited by 22 · see citing works
Ledreux, A., Thomas, S., Hamlett, E. D., Trautman, C. W., Gilmore, A., Hager, E. R., Paredes, D., Margittai, M., Fortea, J., & Granholm, A. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10173931 · Cited by 22 · see citing works
Tau R2 and R3 are essential regions for tau aggregation, seeding and propagation
Annadurai, N., Malina, L., Malohlava, J., Hajdúch, M., & Das, V. (2022) · Biochimie · doi:10.1016/j.biochi.2022.05.013 · Cited by 18 · see citing works
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 · see citing works
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 19 · see citing works
Limorenko, G., Tatlı, M., Rajasekhar, K., Nazarov, S., Weil, M., Schöndorf, D. C., Geist, D., Reinhardt, P., Ehrnhoefer, D. E., Stahlberg, H., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39314-7 · Cited by 19 · see citing works
Total Internal Reflection Tip-Enhanced Raman Spectroscopy of Tau Fibrils
Talaga, D., Cooney, G. S., Ury‐Thiery, V., Fichou, Y., Huang, Y., Lecomte, S., & Bonhommeau, S. (2022) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.2c02786 · Cited by 19 · see citing works
NMR studies of amyloid interactions
Middleton, D. A. (2024) · Progress in Nuclear Magnetic Resonance Spectroscopy · doi:10.1016/j.pnmrs.2024.07.001 · Cited by 18 · see citing works
Kosik, K. S., & Han, S. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-32-9358-8_24 · Cited by 18 · see citing works
Alyenbaawi, H., Allison, W. T., & Mok, S. (2020) · Biomolecules · doi:10.3390/biom10111487 · Cited by 18 · see citing works
Water-directed pinning is key to tau prion formation
Vigers, M. P., Lobo, S., Najafi, S., DuBose, A., Tsay, K., Ganguly, P., Longhini, A. P., Jin, Y., Buratto, S. K., Kosik, K. S., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2421391122 · Cited by 24 · see citing works
Interaction of Tau construct K18 with model lipid membranes
Azouz, M., Feuillie, C., Lafleur, M., Molinari, M., & Lecomte, S. (2021) · Nanoscale Advances · doi:10.1039/d1na00055a · Cited by 16 · see citing works
Tau, RNA, and RNA-Binding Proteins: Complex Interactions in Health and Neurodegenerative Diseases
Lester, E., & Parker, R. (2023) · The Neuroscientist · doi:10.1177/10738584231154551 · Cited by 16 · see citing works
Emerging Trends in Cryo-EM-based Structural Studies of Neuropathological Amyloids
Mishra, S. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168361 · Cited by 16 · see citing works
Gharb, M., Nouralishahi, A., Riazi, A., & Riazi, G. H. (2022) · ACS Omega · doi:10.1021/acsomega.2c03616 · Cited by 15 · see citing works
Pretti, E., & Shell, M. S. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2309995120 · Cited by 15 · see citing works
MAP2 caps tau fibrils and inhibits aggregation
Holden, M. R., Krzesinski, B. J., Weismiller, H. A., Shady, J. R., & Margittai, M. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104891 · Cited by 13 · see citing works
Snow, A. D., Cummings, J. A., Tanzi, R. E., & Lake, T. P. (2021) · Scientific Reports · doi:10.1038/s41598-020-79275-1 · Cited by 13 · see citing works
Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis**
Fernández‐Ramírez, M. D. C., Ng, K. K., Menéndez, M., Laurents, D. V., Hervás, R., & Carrión‐Vázquez, M. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202209252 · Cited by 12 · see citing works
Chemical Imaging of RNA‐Tau Amyloid Fibrils at the Nanoscale Using Tip‐Enhanced Raman Spectroscopy
Cooney, G. S., Talaga, D., Ury‐Thiery, V., Fichou, Y., Huang, Y., Lecomte, S., & Bonhommeau, S. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202314369 · Cited by 12 · see citing works
Nanoscale observation of heparin-mediated self-assembly of chiral tau enantiomers
Chen, W., Chen, Y., Wang, Y., Chen, L., Zhou, S., Li, D., Yin, B., Yang, Z., Yang, Z., & Wang, H. (2024) · Materials Today Physics · doi:10.1016/j.mtphys.2024.101370 · Cited by 12 · see citing works
Landrieu, I., Dupré, E., Sinnaeve, D., Hajjar, L. E., & Smet‐Nocca, C. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.886382 · Cited by 11 · see citing works
Sun, K. T., & Mok, S. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00512 · Cited by 10 · see citing works
dGAE(297–391) Tau Fragment Promotes Formation of Chronic Traumatic Encephalopathy‐Like Tau Filaments
Kitoka, K., Lends, A., Kučinskas, G., Bula, A. L., Krasauskas, L., Smirnovas, V., Žilková, M., Kováčech, B., Škrabana, R., Hritz, J., et al. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202407821 · Cited by 9 · see citing works
Direct Observation of the Self‐Aggregation of R3R4 Bi‐repeat of Tau Protein
Jayan, P., Vahid, A. A., Kizhakkeduth, S. T., Muhammed, S. O. H., Shibina, A. B., & Vijayan, V. (2021) · ChemBioChem · doi:10.1002/cbic.202100013 · Cited by 9 · see citing works
Roles of Nucleic Acids in Protein Folding, Aggregation, and Disease
Litberg, T. J., & Horowitz, S. A. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.3c00695 · Cited by 9 · see citing works
Diverse influences on tau aggregation and implications for disease progressionPreprint
Alstyne, M. V., Pratt, J., & Parker, R. (2025) · Genes & Development · doi:10.1101/gad.352551.124 · Cited by 10 · see citing works
Solvent induced amyloid polymorphism and the uncovering of the elusive class 3 amyloid topology
Dürvanger, Z., Bencs, F., Menyhárd, D. K., Horváth, D., & Perczel, A. (2024) · Communications Biology · doi:10.1038/s42003-024-06621-8 · Cited by 8 · see citing works
Abraham, C. B., Lewkowicz, E., Gursky, O., & Straub, J. E. (2024) · Biochemistry · doi:10.1021/acs.biochem.4c00529 · Cited by 8 · see citing works
Identification of Multicolor Fluorescent Probes for Heterogeneous Aβ Deposits in Alzheimer’s Disease
Mukherjee, A., Al‐Lahham, R., Corkins, M. E., Samanta, S., Schmeichel, A. M., Singer, W., Low, P. A., Govindaraju, T., & Soto, C. A. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.802614 · Cited by 8 · see citing works
Roy, A. S., Marohn, J. A., & Freed, J. H. (2024) · The Journal of Chemical Physics · doi:10.1063/5.0200054 · Cited by 7 · see citing works
Murakami, K., Nguyen, T. H. V., Nagao, C., Mizuguchi, K., & Bitan, G. (2025) · JACS Au · doi:10.1021/jacsau.5c00269 · Cited by 6 · see citing works
Alzheimer’s Disease: Significant Benefit from the Yeast-Based Models
Epremyan, K. K., Mamaev, D. V., & Zvyagilskaya, R. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129791 · Cited by 6 · see citing works
Roy, A. S., Tsay, K., Borbat, P. P., DeStefano, A. J., Han, S., Srivastava, M., & Freed, J. H. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.5c16298 · Cited by 5 · see citing works
Liquid-liquid Phase Separation Modulates the Structural Heterogeneity of Tau Amyloid Fibrils
Ganaie, I. A., & Udgaonkar, J. B. (2026) · Journal of Molecular Biology · doi:10.1016/j.jmb.2026.169737 · Cited by 5 · see citing works
Making tau amyloid models in vitro: a crucial and underestimated challenge
Broc, J., Piersson, C., & Fichou, Y. (2025) · FEBS Letters · doi:10.1002/1873-3468.70022 · Cited by 5 · see citing works
Najar-Ahmadi, S., Haghaei, H., Farajnia, S., Yekta, R., Ezzati, A., & Rashidi, M. (2021) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2021.115924 · Cited by 5 · see citing works
Islam, M., Karim, M. R. U., Argueta, E., Selim, M. N., Wojcikiewicz, E. P., & Du, D. (2025) · Membranes · doi:10.3390/membranes15070208 · Cited by 4 · see citing works
Neander, L., Hannemann, C., Netz, R. R., & Sahoo, A. K. (2025) · JACS Au · doi:10.1021/jacsau.4c00886 · Cited by 4 · see citing works
Namba, N., Ohgita, T., Tamagaki-Asahina, H., Nishitsuji, K., Shimanouchi, T., Sato, T., & Saito, H. (2023) · Scientific Reports · doi:10.1038/s41598-023-45803-y · Cited by 4 · see citing works
Zeng, Z., Tsay, K., Vijayan, V., Frost, M. P., Prakash, S., Quddus, A., Albert, A., Vigers, M. P., Srivastava, M., Woerman, A. L., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.19.549721 · Cited by 4 · see citing works
Montgomery, K. M., Samelson, A. J., & Gestwicki, J. E. (2023) · Israel Journal of Chemistry · doi:10.1002/ijch.202300104 · Cited by 3 · see citing works
Shapeshifter W-Tau Peptide Inhibits Tau Aggregation and Disintegrates Paired Helical Filaments
Domene-Serrano, I., Cuadros, R., García‐Escudero, V., Vallejo-Bedia, F., Santa‐María, I., Vallés‐Saiz, L., Hernández, F., & Ávila, J. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00809 · Cited by 3 · see citing works
Tau Pathology in Neurodegenerative Diseases
Vogels, T., & Hromádka, T. (2021) · Neuromethods · doi:10.1007/978-1-0716-1712-0_4 · Cited by 2 · see citing works
Tau conformers in FTLD-MAPT undergo liquid-liquid phase separation and perturb the nuclear envelopePreprint
Kang, S., Han, Z. Z., Daude, N., McNamara, E., Wohlgemuth, S. L., Safar, J., Mok, S., & Westaway, D. A. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.04.187997 · Cited by 3 · see citing works
Sanchez, J. C., Perez, R. M., Guarino, D. S., Dhavala, D., Baumgardt, J. K., Shaffer, K. D., Kotzbauer, P. T., Mach, R. H., Petersson, E. J., & Wright, E. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.30.662461 · Cited by 3 · see citing works
Pan, T., Tan, Y., Dong, X., Tang, Y., Yang, Z., Chen, Y., & Wei, G. (2025) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5c01590 · Cited by 2 · see citing works
Structural and mechanistic characterization of heparin interactions with tau fibrils
Mon, F., & Straub, J. E. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.111153 · Cited by 2 · see citing works
Structural evidence that RNA contributes to polymorphism of tau amyloid fibrils
Abskharon, R. N. N., Jiang, Y. X., Sawaya, M. R., Ge, P., Zhang, J., Boyer, D. R., Dolinsky, J. L., Pi, J., Cascio, D., Guo, F., et al. (2026) · iScience · doi:10.1016/j.isci.2026.115501 · Cited by 2 · see citing works
Electric Double Layer Phenomena Near Surfaces Irreversibly Trigger Assembly of Tau Protein
Masquelier, E., Hicks, M. H., Watkins, N. B., Lim, N., Yi, J., Morse, D. E., Sepunaru, L., & Gordon, M. J. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.5c23171 · Cited by 2 · see citing works
Local Organization of Biological Membranes Modulates Tau–Lipid Interactions and Fibril formation
Piersson, C., Lublin, V., Duttine, M., Khemtémourian, L., Loquet, A., Mathelié‐Guinlet, M., & Fichou, Y. (2026) · JACS Au · doi:10.1021/jacsau.6c00374 · Cited by 2 · see citing works
Mapping Phase Diagram of Tau-RNA LLPS Under Live Cell Coculturing Conditions
Lin, Y., Fichou, Y., Rauch, J. N., Zhang, X., Kosik, K. S., & Han, S. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2597-2_18 · Cited by 2 · see citing works
Jayaraman, S., Urdaneta, A., Fändrich, M., & Gursky, O. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169007 · Cited by 2 · see citing works
Kinetic Mechanism of Heparin-Induced Fibrillation of α-Synuclein
Ohgita, T., Namba, N., Minami, N., & Saito, H. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00489 · Cited by 3 · see citing works
Structure and function of Full-length Tau
Vallés‐Saiz, L., Domene-Serrano, I., Picher, Á. J., Pérez, M., García‐Escudero, V., Hernández, F., & Ávila, J. (2025) · PLoS ONE · doi:10.1371/journal.pone.0335251 · Cited by 2 · see citing works
dGAE(297-391) tau fragment promotes formation of CTE-like full-length tau filamentsPreprint
Kitoka, K., Lends, A., Kučinskas, G., Bula, A. L., Krasauskas, L., Smirnovas, V., Žilková, M., Kováčech, B., Škrabana, R., Hritz, J., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.01.526268 · Cited by 2 · see citing works
Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis**
Fernández‐Ramírez, M. D. C., Ng, K. K., Menéndez, M., Laurents, D. V., Hervás, R., & Carrión‐Vázquez, M. (2022) · Angewandte Chemie · doi:10.1002/ange.202209252 · Cited by 1 · see citing works
Effect of PHF-1 hyperphosphorylation on the seeding activity of C-terminal Tau fragments
Hajjar, L. E., Boll, E., Cantrelle, F., Bridot, C., Landrieu, I., & Smet‐Nocca, C. (2025) · Scientific Reports · doi:10.1038/s41598-025-91867-3 · Cited by 1 · see citing works
- Authors
- Fichou, Y., Lin, Y., Rauch, J. N., Vigers, M., Zeng, Z., Srivastava, M., Keller, T. J., Freed, J. H., Kosik, K. S., & Han, S.
- Affiliations
- University of California, Santa Barbara (US)
- Cornell University (US)
- Corresponding author
- Fichou, Yann
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-12-11
- Volume
- 115
- Issue
- 52
- Pages
- 13234-13239
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6310788
- OpenAlex
- W2905087948
- Cited by
- 128
- References
- 37
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 12 · 2023: 14 · 2022: 19 · 2021: 24 · 2020: 14 · 2019: 10
- FWCI
- 8.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | National Institutes of Health (R01AG05605, P41GM103521)
- Tau consortium
- Rainwater foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, amyloid fibrils, cofactors, fibril seeding, Alzheimer's disease, tauopathy, 4R tau, neurodegeneration
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Brain, Heparin, Mice, Transgenic, Protein Conformation, Recombinant Proteins, RNA, tau Proteins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
