{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:52:52Z","timestamp":1787161972016,"version":"build-2736575974"},"posted":{"date-parts":[[2026,1,27]]},"group-title":"Neuroscience","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["P30AG062421 (Developmental Project)"],"award-info":[{"award-number":["P30AG062421 (Developmental Project)"]}]},{"name":"NIH","award":["R01NS023868"],"award-info":[{"award-number":["R01NS023868"]}]},{"name":"NIH","award":["R21 AG067772"],"award-info":[{"award-number":["R21 AG067772"]}]},{"name":"NIH","award":["R21 AG072516"],"award-info":[{"award-number":["R21 AG072516"]}]},{"name":"NIH","award":["P30AG062421"],"award-info":[{"award-number":["P30AG062421"]}]},{"name":"Jack Satter Foundation"},{"award":["ALS Transformative Scholar Award"],"award-info":[{"award-number":["ALS Transformative Scholar Award"]}],"id":[{"id":"https:\/\/ror.org\/05c7q3x69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AARG"],"award-info":[{"award-number":["AARG"]}],"id":[{"id":"https:\/\/ror.org\/0375f4d26","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Zenith Award"],"award-info":[{"award-number":["Zenith Award"]}],"id":[{"id":"https:\/\/ror.org\/0375f4d26","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Healey Center","award":["Transformative Award"],"award-info":[{"award-number":["Transformative Award"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Tau aggregation is a defining feature of Alzheimer\u2019s disease and related tauopathies, yet the conformational states of Tau in neurons prior to aggregation remain poorly understood. Existing structural models are derived largely from fibrillar assemblies and provide limited insight into the dynamic, soluble Tau species that initiate pathology. Here, we combine hydrogen\u2013deuterium exchange mass spectrometry with super-resolution imaging and neuronal models to define the conformational ensemble of soluble Tau under physiological and disease-relevant conditions. We show that soluble Tau populates distinct, dynamic conformations characterized by regional stabilization and long-range intramolecular interactions that are invisible to fibril-based structures. Disease-associated perturbations selectively remodel these conformational ensembles, exposing aggregation-prone regions and altering Tau subcellular organization in neurons. Notably, these Tau species inhibit axonal transport, which is essential for neuronal health, linking specific ensemble states to neuronal toxicity. These findings establish soluble Tau conformation as a dynamic, regulatable state that precedes aggregation and encodes disease relevance. By defining the structural logic of Tau before fibril formation, this work provides a framework for understanding early tauopathy mechanisms and for targeting Tau pathology at its earliest stages.<\/jats:p>\n                <jats:sec>\n                  <jats:title>SUMMARY<\/jats:title>\n                  <jats:p>\n                    Tau pathology is a hallmark of Alzheimer\u2019s disease (AD) and related dementias (ADRDs). Although Tau is often described as intrinsically disordered, it is a dynamic protein with distinct but poorly defined conformations. Here we conduct a systematic time-resolved structure-function analysis of normal and pathologic Tau, including hyperphosphorylated, mutant Tau, and posttranslational-modification-mimetic Tau. To characterize dynamic conformational changes of Tau, we combined state-of-the-art hydrogen deuterium exchange mass spectrometry with structured illumination microscopy, demonstrating a novel Tau-MT binding mode: \u201cdynamic oscillation\u201d. To correlate Tau structure with neuronal function, we evaluated axonal transport as a sensitive readout of neuronal health. Many toxic Tau forms share a common signature of increased exposure of the N-terminal phosphate activating domain (PAD)\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Aberrant exposure of PAD correlates with Tau pathology and axonal transport defects. Tau phosphorylation at S262 alone is sufficient to alter Tau-microtubule interactions beyond R1-R4 motifs, globally changing Tau conformation, disrupting \u201cdynamic oscillation\u201d on MTs, and inhibiting axonal transport. Frontotemporal dementia-associated P301L-Tau remains associated with microtubules but also inhibits axonal transport. Our results reveal a well-defined conformation of soluble WT Tau in neurons and its highly dynamic interaction with microtubules, altered by AD\/ADRD-Tau forms. Our multidisciplinary approach comprising biochemical manipulations, innovative MS tools, advanced microscopy, cellular assays, and mouse and human data pair Tau conformations with distinct neuronal functions and pathologies in health and disease.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.26.701882","type":"posted-content","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T20:10:12Z","timestamp":1769544612000},"source":"Crossref","is-referenced-by-count":2,"title":["Dynamic conformational ensembles of soluble Tau encode neuronal toxicity prior to aggregation"],"prefix":"10.64898","author":[{"given":"Florian","family":"Georgescauld","sequence":"first","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, MS 412TF, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Okekenwa","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16 Street, Charlestown, MA, 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanner","family":"Boyd","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16 Street, Charlestown, MA, 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Donahue","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16 Street, Charlestown, MA, 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noe","family":"Quittot","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16 Street, Charlestown, MA, 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16 Street, Charlestown, MA, 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanyun","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital and Harvard Medical School, 114 16 Street, Charlestown, MA, 02129"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Brady","sequence":"additional","affiliation":[{"name":"Marine Biology Laboratory, 7 MBL Street, Woods Hole, MA 02543"},{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S. 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