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Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner

Mosconi, Michele LU ; Leonardi, Chiara LU ; Armour-Garb, Zev ; Rocutto, Beatrice ; Beeg, Marten ; Meisl, Georg ; Ortigosa-Pascual, Lei LU orcid ; Broggini, Luca ; Salmona, Mario and Ricagno, Stefano , et al. (2026) In Proceedings of the National Academy of Sciences of the United States of America 123(13).
Abstract

Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer’s disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between Aβ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of Aβ42 in a fold-specific manner with enzyme-like kinetics. In... (More)

Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer’s disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between Aβ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of Aβ42 in a fold-specific manner with enzyme-like kinetics. In particular, CTE fibrils exhibit the highest catalytic activity and constrain Aβ42 polymorphism, suggesting templating effects. Moreover, PHF and CTE tau fibrils increase Aβ42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans, preserving fold-dependent reactivities. Our findings shed light on the molecular mechanisms of heterotypic interaction between amyloidogenic proteins in disease-relevant conditions, highlighting the role of amyloid structure and recognition mechanisms as key determinants. These results offer insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here might be used as a blueprint for structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, amyloid-β, chronic traumatic encephalopathy, protein aggregation, tau
in
Proceedings of the National Academy of Sciences of the United States of America
volume
123
issue
13
article number
e2532775123
publisher
National Academy of Sciences
external identifiers
  • pmid:41880569
  • scopus:105034366988
ISSN
0027-8424
DOI
10.1073/pnas.2532775123
language
English
LU publication?
yes
additional info
Publisher Copyright: Copyright © 2026 the Author(s).
id
bb3a0db0-38ea-4b1b-9dfe-3b85fe30da0e
date added to LUP
2026-05-25 16:22:43
date last changed
2026-05-29 15:14:00
@article{bb3a0db0-38ea-4b1b-9dfe-3b85fe30da0e,
  abstract     = {{<p>Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer’s disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between Aβ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of Aβ42 in a fold-specific manner with enzyme-like kinetics. In particular, CTE fibrils exhibit the highest catalytic activity and constrain Aβ42 polymorphism, suggesting templating effects. Moreover, PHF and CTE tau fibrils increase Aβ42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans, preserving fold-dependent reactivities. Our findings shed light on the molecular mechanisms of heterotypic interaction between amyloidogenic proteins in disease-relevant conditions, highlighting the role of amyloid structure and recognition mechanisms as key determinants. These results offer insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here might be used as a blueprint for structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.</p>}},
  author       = {{Mosconi, Michele and Leonardi, Chiara and Armour-Garb, Zev and Rocutto, Beatrice and Beeg, Marten and Meisl, Georg and Ortigosa-Pascual, Lei and Broggini, Luca and Salmona, Mario and Ricagno, Stefano and Knowles, Tuomas P.J. and Diomede, Luisa}},
  issn         = {{0027-8424}},
  keywords     = {{Alzheimer’s disease; amyloid-β; chronic traumatic encephalopathy; protein aggregation; tau}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{13}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner}},
  url          = {{http://dx.doi.org/10.1073/pnas.2532775123}},
  doi          = {{10.1073/pnas.2532775123}},
  volume       = {{123}},
  year         = {{2026}},
}