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Cited by 192Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo

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Vasconcelos, Bruno, Stancu, Ilie-Cosmin, Buist, Arjan, Bird, Matthew, Wang, Peng, Vanoosthuyse, Alexandre, Van Kolen, Kristof, Verheyen, An +5 more·2016·Acta Neuropathologica
DOI 10.1007/s00401-015-1525-xPMC PMC4789256
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Abstract

Genetic, clinical, histopathological and biomarker data strongly support Beta-amyloid (Aβ) induced spreading of Tau-pathology beyond entorhinal cortex (EC), as a crucial process in conversion from preclinical cognitively normal to Alzheimer's Disease (AD), while the underlying mechanism remains unclear. In vivo preclinical models have reproducibly recapitulated Aβ-induced Tau-pathology. Tau pathology was thereby also induced by aggregated Aβ, in functionally connected brain areas, reminiscent of a prion-like seeding process. In this work we demonstrate, that pre-aggregated Aβ can directly induce Tau fibrillization by cross-seeding, in a cell-free assay, comparable to that demonstrated before for alpha-synuclein and Tau. We furthermore demonstrate, in a well-characterized cellular Tau-aggregation assay that Aβ-seeds cross-seeded Tau-pathology and strongly catalyzed pre-existing Tau-aggregation, reminiscent of the pathogenetic process in AD. Finally, we demonstrate that heterotypic seeded Tau by pre-aggregated Aβ provides efficient seeds for induction and propagation of Tau-pathology in vivo. Prion-like, heterotypic seeding of Tau fibrillization by Aβ, providing potent seeds for propagating Tau pathology in vivo, as demonstrated here, provides a compelling molecular mechanism for Aβ-induced propagation of Tau-pathology, beyond regions with pre-existing Tau-pathology (entorhinal cortex/locus coeruleus). Cross-seeding along functional connections could thereby resolve the initial spatial dissociation between amyloid- and Tau-pathology, and preferential propagation of Tau-pathology in regions with pre-existing 'silent' Tau-pathology, by conversion of a 'silent' Tau pathology to a 'spreading' Tau-pathology, observed in AD.

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  • Pre-aggregated Aβ is able to induce fibrillization of tau both in vitro and in vivo.

    “Related findings were reported by Vasconselos and colleagues, showing that pre-aggregated Aβ is able to induce fibrillization of tau both in vitro and in vivo [32], and interestingly, passive immunization against Aβ in the 3xTg mouse model not only reduced extracellular amyloid plaques but also resulted in decreased tau pathology [33].”

    From Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau (2021) · cites this paper as [32]

    The Results section on the cell-free assay reports that pre-aggregated Aβ directly seeded tau fibrillization in vitro. The in vivo Results instead report fibrillary tau pathology after injection of Aβ-seeded tau aggregates into transgenic mice; they do not establish that pre-aggregated Aβ itself induced tau fibrillization in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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  • Aβ deposits or associated proteins can help in seeding and neuroanatomic transmission of a specific type of misfolded tau or its derivatives.

    “It is also possible that Aβ deposits or its associated proteins can somehow help in seeding and neuroanatomic transmission of a specific type of misfolded tau or its derivatives (28).”

    From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [28]

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Research works printed but not linked: 41

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Authors
Vasconcelos, B., Stancu, I.-C., Buist, A., Bird, M., Wang, P., Vanoosthuyse, A., Van Kolen, K., Verheyen, A., Kienlen-Campard, P., Octave, J.-N., Baatsen, P., Moechars, D., & Dewachter, I.
Affiliations
  • UCLouvain (BE)
  • Janssen (Belgium) (BE)
  • KU Leuven (BE)
Corresponding author
Dewachter, Ilse
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2016-01-06
Volume
131
Issue
4
Pages
549-569
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-015-1525-x
PMC
PMC4789256
OpenAlex
W2226896309
Cited by
192
References
61
Citations by year
2026: 8 · 2025: 24 · 2024: 21 · 2023: 18 · 2022: 13 · 2021: 20 · 2020: 26 · 2019: 14 · 2018: 22 · 2017: 18 · 2016: 8
FWCI
16.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Libraries (submittedVersion)
  • Document Server@UHasselt (UHasselt) (submittedVersion, other-oa)
Funders
Fonds De La Recherche Scientifique - FNRS (BE)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tau fibrillization, cross-seeding, prion-like seeding, Alzheimer's disease, entorhinal cortex, locus coeruleus, brain functional connectivity, preclinical Alzheimer's disease
MeSH terms
Prion Proteins, Analysis of Variance, Animals, Disease Models, Animal, Humans, Immunohistochemistry, Mice, Transgenic, Mutation, Transfection, Amyloid beta-Peptides, tau Proteins, Tauopathies, Green Fluorescent Proteins, Presenilin-1, HEK293 Cells, Protein Aggregation, Pathological

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