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Modulating the self-assembly process and inhibiting formation and spreading of such toxic species are promising strategies for therapy development. A challenge in investigating tau self-assembly in vitro is that, unlike most amyloidogenic proteins, tau does not aggregate in the absence of posttranslational modifications (PTM), aggregation inducers, or preformed seeds. The most common induction method is addition of polyanions, such as heparin; yet, this artificial system may not represent adequately tau self-assembly in vivo, which is driven by aberrant phosphorylation and other PTMs, potentially leading to in vitro data that do not reflect the behavior of tau and its interaction with modulators in vivo. To tackle these challenges, methods for in vitro phosphorylation of tau to produce aggregation-competent forms recently have been introduced (Despres et al. (2017) Proc. Natl. Acad. Sci. U.S.A., 114, 9080\u22129085.). However, the oligomerization, seeding, and interaction with assembly modulators of the different forms of tau have not been studied to date. To address these knowledge gaps, we compared here side-by-side the self-assembly and seeding activity of heparin-induced tau with two forms of in vitro phosphorylated tau and tested how the molecular tweezer CLR01, a negatively charged compound, affected these processes. Tau was phosphorylated by incubation either with activated extracellular signal-regulated kinase 2 or with a whole rat brain extract. Seeding activity was measured using a fluorescence-resonance energy transfer-based biosensor-cell method. We also used solution-state NMR to investigate the binding sites of CLR01 on tau and how they were impacted by phosphorylation. Our systematic structure\u2013activity relationship study demonstrates that heparin-induced tau behaves differently from in vitro phosphorylated tau. The aggregation rates of the different forms are distinct as is the intracellular localization of the induced aggregates, which resemble brain-derived tau strains suggesting that heparin-induced tau and in vitro phosphorylated tau have different conformations, properties, and activities. CLR01 inhibits aggregation and seeding of both heparin-induced and in vitro phosphorylated tau dose-dependently, although heparin induction interferes with the interaction between CLR01 and tau.<\/jats:p>","DOI":"10.1021\/acschembio.9b00325","type":"journal-article","created":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T16:04:41Z","timestamp":1556813081000},"page":"1363-1379","source":"Crossref","is-referenced-by-count":61,"title":["Major Differences between the Self-Assembly and Seeding\nBehavior of Heparin-Induced and in Vitro Phosphorylated Tau and Their\nModulation by Potential Inhibitors"],"prefix":"10.1021","volume":"14","author":[{"given":"Cle\u0301ment","family":"Despres","sequence":"first","affiliation":[{"name":"Lille University CNRS UMR 8576, UGSF , ,","place":["Lille, France, F-59000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Di","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franc\u0327ois-Xavier","family":"Cantrelle","sequence":"additional","affiliation":[{"name":"Lille University CNRS UMR 8576, UGSF , ,","place":["Lille, France, F-59000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zizheng","family":"Li","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Huvent","sequence":"additional","affiliation":[{"name":"Lille University CNRS UMR 8576, UGSF , ,","place":["Lille, France, F-59000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Be\u0301atrice","family":"Chambraud","sequence":"additional","affiliation":[{"name":"UMR 1195 Inserm, University Paris XI , ,","place":["Le Kremlin Bice\u0302tre, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"Rensselaer Polytechnic Institute , , , ,","place":["Troy, New York, United States, 12180"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianle","family":"Chen","sequence":"additional","affiliation":[{"name":"Rensselaer Polytechnic Institute , , , ,","place":["Troy, New York, United States, 12180"]},{"name":"Zhejiang University , , , ,","place":["Hangzhou, Zhejiang, China, 310029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6439-7735","authenticated-orcid":true,"given":"Shiguo","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhejiang University , , , ,","place":["Hangzhou, Zhejiang, China, 310029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Lippens","sequence":"additional","affiliation":[{"name":"Lille University CNRS UMR 8576, UGSF , ,","place":["Lille, France, F-59000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2803-3704","authenticated-orcid":true,"given":"Fuming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Rensselaer Polytechnic Institute , , , ,","place":["Troy, New York, United States, 12180"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2219-5833","authenticated-orcid":true,"given":"Robert","family":"Linhardt","sequence":"additional","affiliation":[{"name":"Rensselaer Polytechnic Institute , , , ,","place":["Troy, New York, United States, 12180"]},{"name":"Rensselaer Polytechnic Institute , , , ,","place":["Troy, New York, United States, 12180"]},{"name":"Zhejiang University , , , ,","place":["Hangzhou, Zhejiang, China, 310029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5165-7959","authenticated-orcid":true,"given":"Chunyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Rensselaer Polytechnic Institute , , , ,","place":["Troy, New York, United States, 12180"]},{"name":"Rensselaer Polytechnic Institute , , , ,","place":["Troy, New York, United States, 12180"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank-Gerrit","family":"Kla\u0308rner","sequence":"additional","affiliation":[{"name":"University of Duisburg-Essen , , ,","place":["Essen, Germany, 45141"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-6362","authenticated-orcid":true,"given":"Thomas","family":"Schrader","sequence":"additional","affiliation":[{"name":"University of Duisburg-Essen , , ,","place":["Essen, Germany, 45141"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Landrieu","sequence":"additional","affiliation":[{"name":"Lille University CNRS UMR 8576, UGSF , ,","place":["Lille, France, F-59000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7046-3754","authenticated-orcid":true,"given":"Gal","family":"Bitan","sequence":"additional","affiliation":[{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]},{"name":"University of California , , , ,","place":["Los Angeles, California, United States, 90095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Smet-Nocca","sequence":"additional","affiliation":[{"name":"Lille University CNRS UMR 8576, UGSF , ,","place":["Lille, France, F-59000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,5,2]]},"reference":[{"key":"2026090113075103500_cit1","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/nrn2194","article-title":"Tau-Mediated Neurodegeneration in\nAlzheimer\u2019s Disease and Related Disorders","volume":"8","author":"Ballatore","year":"2007","journal-title":"Nat. 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Disord."},{"key":"2026090113075103500_cit10","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/0197-4580(95)00021-6","article-title":"Staging of Alzheimer\u2019s Disease-Related Neurofibrillary Changes","volume":"16","author":"Braak","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"2026090113075103500_cit11","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1021\/cn500143n","article-title":"Advances in\nTherapeutics for Neurodegenerative\nTauopathies: Moving toward the Specific Targeting of the Most Toxic\nTau Species","volume":"5","author":"Gerson","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"2026090113075103500_cit12","doi-asserted-by":"publisher","first-page":"e1001080","DOI":"10.1371\/journal.pbio.1001080","article-title":"Towards a Pharmacophore for Amyloid","volume":"9","author":"Landau","year":"2011","journal-title":"PLoS Biol."},{"key":"2026090113075103500_cit13","doi-asserted-by":"publisher","first-page":"9034","DOI":"10.1073\/pnas.1530287100","article-title":"Tau Filaments from Human Brain and from in Vitro Assembly\nof Recombinant Protein Show Cross-Beta Structure","volume":"100","author":"Berriman","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. 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A."},{"key":"2026090113075103500_cit16","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/nature23002","article-title":"Cryo-EM Structures of Tau Filaments from Alzheimer\u2019s\nDisease","volume":"547","author":"Fitzpatrick","year":"2017","journal-title":"Nature"},{"key":"2026090113075103500_cit17","doi-asserted-by":"publisher","first-page":"E313","DOI":"10.1073\/pnas.1212100110","article-title":"The Fuzzy\nCoat of Pathological Human Tau Fibrils Is a Two-Layered Polyelectrolyte\nBrush","volume":"110","author":"Wegmann","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026090113075103500_cit18","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/0896-6273(92)90117-V","article-title":"Tau Proteins of\nAlzheimer Paired Helical Filaments: Abnormal Phosphorylation of All\nSix Brain Isoforms","volume":"8","author":"Goedert","year":"1992","journal-title":"Neuron"},{"key":"2026090113075103500_cit19","doi-asserted-by":"crossref","first-page":"24374","DOI":"10.1016\/S0021-9258(20)80536-5","article-title":"Microtubule-Associated\nProtein Tau. Abnormal Phosphorylation\nof a Non-Paired Helical Filament Pool in Alzheimer Disease","volume":"268","author":"Ko\u0308pke","year":"1993","journal-title":"J. Biol. Chem."},{"key":"2026090113075103500_cit20","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/0006-8993(92)91476-U","article-title":"Phosphate Analysis and Dephosphorylation\nof Modified Tau Associated with Paired Helical Filaments","volume":"597","author":"Ksiezak-Reding","year":"1992","journal-title":"Brain Res."},{"key":"2026090113075103500_cit21","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/0197-4580(95)00027-C","article-title":"Hyperphosphorylation\nof Tau in PHF","volume":"16","author":"Morishima-Kawashima","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"2026090113075103500_cit22","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1074\/jbc.270.2.823","article-title":"Proline-Directed and Non-Proline-Directed\nPhosphorylation of PHF-Tau","volume":"270","author":"Morishima-Kawashima","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2026090113075103500_cit23","doi-asserted-by":"publisher","first-page":"2465","DOI":"10.1046\/j.1471-4159.1998.71062465.x","article-title":"New Phosphorylation Sites Identified\nin Hyperphosphorylated\nTau (Paired Helical Filament-Tau) from Alzheimer\u2019s Disease\nBrain Using Nanoelectrospray Mass Spectrometry","volume":"71","author":"Hanger","year":"1998","journal-title":"J. Neurochem."},{"key":"2026090113075103500_cit24","doi-asserted-by":"publisher","first-page":"23645","DOI":"10.1074\/jbc.M703269200","article-title":"Novel Phosphorylation\nSites in Tau from Alzheimer Brain Support a Role for Casein Kinase\n1 in Disease Pathogenesis","volume":"282","author":"Hanger","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2026090113075103500_cit25","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/0304-3940(92)90774-2","article-title":"Glycogen\nSynthase Kinase-3 Induces Alzheimer\u2019s Disease-like Phosphorylation\nof Tau: Generation of Paired Helical Filament Epitopes and Neuronal\nLocalisation of the Kinase","volume":"147","author":"Hanger","year":"1992","journal-title":"Neurosci. Lett."},{"key":"2026090113075103500_cit26","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1002\/j.1460-2075.1992.tb05204.x","article-title":"The Switch of Tau Protein to an Alzheimer-like\nState Includes the Phosphorylation of Two Serine-Proline Motifs Upstream\nof the Microtubule Binding Region","volume":"11","author":"Biernat","year":"1992","journal-title":"EMBO J."},{"key":"2026090113075103500_cit27","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1042\/bj3010871","article-title":"Epitope Mapping of Monoclonal Antibodies\nto the Paired Helical Filaments of Alzheimer\u2019s Disease: Identification\nof Phosphorylation Sites in Tau Protein","volume":"301","author":"Goedert","year":"1994","journal-title":"Biochem.\nJ."},{"key":"2026090113075103500_cit28","doi-asserted-by":"publisher","first-page":"3549","DOI":"10.1021\/bi981874p","article-title":"Phosphorylation\nThat Detaches Tau Protein from Microtubules\n(Ser262, Ser214) Also Protects It against Aggregation into Alzheimer\nPaired Helical Filaments","volume":"38","author":"Schneider","year":"1999","journal-title":"Biochemistry"},{"key":"2026090113075103500_cit29","doi-asserted-by":"publisher","first-page":"7742","DOI":"10.1074\/jbc.M115.700914","article-title":"Characterization of\nNeuronal Tau Protein as a Target of Extracellular Signal-Regulated\nKinase","volume":"291","author":"Qi","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2026090113075103500_cit30","doi-asserted-by":"publisher","first-page":"9080","DOI":"10.1073\/pnas.1708448114","article-title":"Identification\nof the Tau Phosphorylation Pattern That Drives Its Aggregation","volume":"114","author":"Despres","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026090113075103500_cit31","doi-asserted-by":"publisher","first-page":"4506","DOI":"10.1073\/pnas.85.12.4506","article-title":"Isolation of a Fragment\nof Tau Derived from the Core of the Paired\nHelical Filament of Alzheimer Disease","volume":"85","author":"Wischik","year":"1988","journal-title":"Proc.\nNatl. Acad. Sci. U. S. A."},{"key":"2026090113075103500_cit32","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/978-1-4939-6598-4_8","article-title":"Assays\nfor the Screening and Characterization of Tau Aggregation Inhibitors","volume":"1523","author":"Rickard","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"2026090113075103500_cit33","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1002\/j.1460-2075.1993.tb05665.x","article-title":"Molecular Characterization\nof the\nMinimal Protease Resistant Tau Unit of the Alzheimer\u2019s Disease\nPaired Helical Filament","volume":"12","author":"Novak","year":"1993","journal-title":"EMBO J."},{"key":"2026090113075103500_cit34","doi-asserted-by":"publisher","first-page":"11213","DOI":"10.1073\/pnas.93.20.11213","article-title":"Selective\nInhibition of Alzheimer Disease-like Tau Aggregation by Phenothiazines","volume":"93","author":"Wischik","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026090113075103500_cit35","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1083\/jcb.118.3.573","article-title":"Alzheimer-like Paired Helical Filaments\nand Antiparallel\nDimers Formed from Microtubule-Associated Protein Tau in Vitro","volume":"118","author":"Wille","year":"1992","journal-title":"J. Cell Biol."},{"key":"2026090113075103500_cit36","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/383550a0","article-title":"Assembly of Microtubule-Associated Protein Tau into\nAlzheimer-like Filaments Induced by Sulphated Glycosaminoglycans","volume":"383","author":"Goedert","year":"1996","journal-title":"Nature"},{"key":"2026090113075103500_cit37","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1046\/j.1471-4159.1996.67031183.x","article-title":"Polymerization of Tau into Filaments in the Presence of Heparin:\nThe Minimal Sequence Required for Tau-Tau Interaction","volume":"67","author":"Pe\u0301rez","year":"1996","journal-title":"J. Neurochem."},{"key":"2026090113075103500_cit38","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/S0014-5793(96)01386-5","article-title":"RNA Stimulates\nAggregation of Microtubule-Associated\nProtein Tau into Alzheimer-like Paired Helical Filaments","volume":"399","author":"Kampers","year":"1996","journal-title":"FEBS Lett."},{"key":"2026090113075103500_cit39","first-page":"2181","article-title":"Free Fatty Acids Stimulate the Polymerization\nof Tau\nand Amyloid Beta Peptides. In Vitro Evidence for a Common Effector\nof Pathogenesis in Alzheimer\u2019s Disease","volume":"150","author":"Wilson","year":"1997","journal-title":"Am. J. Pathol."},{"key":"2026090113075103500_cit40","doi-asserted-by":"publisher","first-page":"25644","DOI":"10.1074\/jbc.M301663200","article-title":"Anionic Micelles and Vesicles Induce\nTau Fibrillization in Vitro","volume":"278","author":"Chirita","year":"2003","journal-title":"J. Biol. 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