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Reversibility and β-sheet formation are decoupled in tau condensate aging.

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Title: Reversibility and β-sheet formation are decoupled in tau condensate aging.
Authors: Fischer, Charlotte M.1, Edu, Irina A.1, Šneideris, Tomas1, Baronaite, Ieva1, Toprakcioglu, Zenon1, Deck, Leif-Thore1, Qian, Daoyuan1, Scrutton, Rob1, Dreyer, Lasse1,2, Wen, Jitao3, Otzen, Daniel E.2, Wu, Si3,4, Perrett, Sarah1,3, Knowles, Tuomas P. J.1 tpjk2@cam.ac.uk
Source: Proceedings of the National Academy of Sciences of the United States of America. 3/17/2026, Vol. 123 Issue 11, p1-10. 30p.
Subjects: Tau proteins, Reversible phase transitions, Amino acid sequence, Alzheimer's disease, Neurofibrillary tangles, Tertiary structure, Neurodegeneration
Abstract: Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function in Alzheimer's disease and are strongly associated with cognitive decline. Early events in tau aggregation are increasingly linked to the formation of biomolecular condensates, which lower the energetic barriers to pathological aggregation by acting as intermediates that transition into insoluble assemblies, a mechanism also implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite growing evidence for this pathway, the molecular basis by which reversible condensates evolve into irreversible, pathogenic aggregates has remained unclear. Here, we map the phase behavior, structural transitions, and thermodynamic reversibility of tau during condensate aging. Our results reveal that the two hallmark features of the pathological end state, ß-sheet enrichment and irreversible aggregation, emerge at different rates and occupy distinct regions of the phase space, indicating that these properties are mechanistically uncoupled. Notably, we identify tau condensate phases that are ß-sheet rich yet thermodynamically reversible, as well as irreversible intermediates that lack ß-sheet structure. These findings expand the landscape of tau aggregate species beyond a simple linear progression toward fibrils and highlight a diverse array of intermediates with distinct structural and thermodynamic properties. This decoupling of structure and irreversibility has important implications for understanding tau aggregation mechanisms and may offer targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
An: 192860041
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: Reversibility and β-sheet formation are decoupled in tau condensate aging.
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  Data: <searchLink fieldCode="AR" term="%22Fischer%2C+Charlotte+M%2E%22">Fischer, Charlotte M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Edu%2C+Irina+A%2E%22">Edu, Irina A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Šneideris%2C+Tomas%22">Šneideris, Tomas</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Baronaite%2C+Ieva%22">Baronaite, Ieva</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Toprakcioglu%2C+Zenon%22">Toprakcioglu, Zenon</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Deck%2C+Leif-Thore%22">Deck, Leif-Thore</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Qian%2C+Daoyuan%22">Qian, Daoyuan</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Scrutton%2C+Rob%22">Scrutton, Rob</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Dreyer%2C+Lasse%22">Dreyer, Lasse</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Wen%2C+Jitao%22">Wen, Jitao</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Otzen%2C+Daniel+E%2E%22">Otzen, Daniel E.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Wu%2C+Si%22">Wu, Si</searchLink><relatesTo>3,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Perrett%2C+Sarah%22">Perrett, Sarah</searchLink><relatesTo>1,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Knowles%2C+Tuomas+P%2E+J%2E%22">Knowles, Tuomas P. J.</searchLink><relatesTo>1</relatesTo><i> tpjk2@cam.ac.uk</i>
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  Data: <searchLink fieldCode="DE" term="%22Tau+proteins%22">Tau proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Reversible+phase+transitions%22">Reversible phase transitions</searchLink><br /><searchLink fieldCode="DE" term="%22Amino+acid+sequence%22">Amino acid sequence</searchLink><br /><searchLink fieldCode="DE" term="%22Alzheimer's+disease%22">Alzheimer's disease</searchLink><br /><searchLink fieldCode="DE" term="%22Neurofibrillary+tangles%22">Neurofibrillary tangles</searchLink><br /><searchLink fieldCode="DE" term="%22Tertiary+structure%22">Tertiary structure</searchLink><br /><searchLink fieldCode="DE" term="%22Neurodegeneration%22">Neurodegeneration</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function in Alzheimer's disease and are strongly associated with cognitive decline. Early events in tau aggregation are increasingly linked to the formation of biomolecular condensates, which lower the energetic barriers to pathological aggregation by acting as intermediates that transition into insoluble assemblies, a mechanism also implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite growing evidence for this pathway, the molecular basis by which reversible condensates evolve into irreversible, pathogenic aggregates has remained unclear. Here, we map the phase behavior, structural transitions, and thermodynamic reversibility of tau during condensate aging. Our results reveal that the two hallmark features of the pathological end state, ß-sheet enrichment and irreversible aggregation, emerge at different rates and occupy distinct regions of the phase space, indicating that these properties are mechanistically uncoupled. Notably, we identify tau condensate phases that are ß-sheet rich yet thermodynamically reversible, as well as irreversible intermediates that lack ß-sheet structure. These findings expand the landscape of tau aggregate species beyond a simple linear progression toward fibrils and highlight a diverse array of intermediates with distinct structural and thermodynamic properties. This decoupling of structure and irreversibility has important implications for understanding tau aggregation mechanisms and may offer targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2522993123
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        Text: English
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        PageCount: 30
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      – SubjectFull: Tau proteins
        Type: general
      – SubjectFull: Reversible phase transitions
        Type: general
      – SubjectFull: Amino acid sequence
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      – SubjectFull: Alzheimer's disease
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      – SubjectFull: Neurofibrillary tangles
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      – SubjectFull: Tertiary structure
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      – SubjectFull: Neurodegeneration
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              Text: 3/17/2026
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