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Cited by 43Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Astrocytic uptake of neuronal corpses promotes cell‐to‐cell spreading of tau pathology

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Mothes, Tobias, Portal, Benjamin, Konstantinidis, Evangelos, Eltom, Khalid, Libard, Sylwia, Streubel-Gallasch, Linn, Ingelsson, Martin, Rostami, Jinar +2 more·2023·Acta Neuropathologica Communications
DOI 10.1186/s40478-023-01589-8PMC PMC10276914
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Abstract

Tau deposits in astrocytes are frequently found in Alzheimer’s disease (AD) and other tauopathies. Since astrocytes do not express tau, the inclusions have been suggested to be of neuronal origin. However, the mechanisms behind their appearance and their relevance for disease progression remain unknown. Here we demonstrate, using a battery of experimental techniques that human astrocytes serve as an intermediator, promoting cell-to-cell spreading of pathological tau. Human astrocytes engulf and process, but fail to fully degrade dead neurons with tau pathology, as well as synthetic tau fibrils and tau aggregates isolated from AD brain tissue. Instead, the pathogenic tau is spread to nearby cells via secretion and tunneling nanotube mediated transfer. By performing co-culture experiments we could show that tau-containing astrocytes induce tau pathology in healthy human neurons directly. Furthermore, our results from a FRET based seeding assay, demonstrated that the tau proteoforms secreted by astrocytes have an exceptional seeding capacity, compared to the original tau species engulfed by the cells. Taken together, our study establishes a central role for astrocytes in mediating tau pathology, which could be of relevance for identifying novel treatment targets for AD and other tauopathies.

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  • Astrocyte cell projections are critical for cellular communication and for the clearance of toxic oligomers such as tau.

    “Astrocyte cell projections, or extensions, are critical for cellular communication 29 and for the clearance of toxic oligomers such as tau. 30”

    From Protective mechanisms against Alzheimer's disease in APOE3‐Christchurch homozygous astrocytes (2025) · cites this paper as [30]

    Citation 30 is attached to the claim that astrocyte extensions clear toxic tau. The Discussion says astrocytes are unable to clear engulfed tau aggregates; instead, ineffective degradation promotes the cell-to-cell spread of pathological tau. The paper therefore makes the contrary point about clearance. (LLM, conf=0.89)

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Cited by

Sorted by citations

Authors
Mothes, T., Portal, B., Konstantinidis, E., Eltom, K., Libard, S., Streubel-Gallasch, L., Ingelsson, M., Rostami, J., Lindskog, M., & Erlandsson, A.
Affiliations
Uppsala University (SE)
Corresponding author
Erlandsson, Anna
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2023-06-17
Volume
11
Issue
1
Pages
97-97
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-023-01589-8
PMC
PMC10276914
OpenAlex
W4381094183
Cited by
43
References
10
Citations by year
2026: 14 · 2025: 12 · 2024: 15 · 2023: 2
FWCI
7.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alzheimerfonden (AF-968209)
  • Hjärnfonden (FO2021-0174)
  • Åhlén-stiftelsen (213021)
  • Stiftelsen för Gamla Tjänarinnor (2021-01171)
  • O. E. och Edla Johanssons Vetenskapliga Stiftelse (2021)
  • Stiftelsen Olle Engkvist Byggmästare (215-0399)
  • Gun och Bertil Stohnes Stiftelse (2021)
  • Vetenskapsrådet (2021-02563)
  • Uppsala University
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
astrocytes, tau pathology, Alzheimer's disease, tauopathy, cell-to-cell transmission, tunneling nanotubes, co-culture
MeSH terms
Alzheimer Disease, Astrocytes, Brain, Humans, Neurons, tau Proteins, Tauopathies

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