{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:24:03Z","timestamp":1783578243797,"version":"3.55.0"},"reference-count":60,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel neurotoxic pT231-tau conformer in human AD neurons, distinct from both cis and trans conformations, which we propose as the gauche pT231-tau conformer. Notably, levels of this conformer were elevated in neurons subjected to aging-associated stress. In order to confirm the stress, we examined p21 accumulation in both human iPSC-derived and mouse cortical neurons under aging stress. Targeted elimination of the gauche pT231-tau conformer mitigated neurodegeneration in human AD cultures. These findings suggest the gauche pT231-tau conformer plays a key role in tau-mediated neurodegeneration and may be a potential therapeutic target for AD.<\/jats:p>","DOI":"10.3390\/biom15040585","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T08:11:39Z","timestamp":1744704699000},"page":"585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Novel Phosphorylated Tau Conformer Implicated in the Tauopathy Pathogenesis of Human Neurons"],"prefix":"10.3390","volume":"15","author":[{"given":"Nahid","family":"Tofigh","sequence":"first","affiliation":[{"name":"Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran 13561-457, Iran"},{"name":"Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1446-2051","authenticated-orcid":false,"given":"Sadaf","family":"Agahi","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran 14768-211, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gholamhossein","family":"Riazi","sequence":"additional","affiliation":[{"name":"Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran 13561-457, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahboobeh","family":"Ghalamkar Moazzam","sequence":"additional","affiliation":[{"name":"Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koorosh","family":"Shahpasand","sequence":"additional","affiliation":[{"name":"Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148, Iran"},{"name":"Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55414, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"ref_1","first-page":"1598","article-title":"Alzheimer\u2019s disease facts and figures","volume":"19","author":"Better","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.1038\/s41380-021-01249-0","article-title":"The Amyloid-\u03b2 Pathway in Alzheimer\u2019s Disease","volume":"26","author":"Hampel","year":"2021","journal-title":"Mol. 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