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Astrocytic uptake of neuronal corpses promotes cell-to-cell spreading of tau pathology
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0009-0001-5223-0575
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.ORCID iD: 0000-0002-5648-4169
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0002-8753-347x
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0002-7427-9927
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2023 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 11, no 1, article id 97Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023. Vol. 11, no 1, article id 97
Keywords [en]
Alzheimer's disease, Tau, Astrocytes, Neurons, Cell-to-cell spreading, hiPSCs
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-506917DOI: 10.1186/s40478-023-01589-8ISI: 001007228100001PubMedID: 37330529OAI: oai:DiVA.org:uu-506917DiVA, id: diva2:1778031
Funder
Uppsala UniversitySwedish Research Council, 2021–02563Alzheimerfonden, AF‑968209Åhlén-stiftelsen, 213021The Swedish Brain Foundation, FO2021‑0174Stiftelsen Gamla Tjänarinnor, 2021–01171O.E. och Edla Johanssons vetenskapliga stiftelseOlle Engkvists stiftelse, 215–0399Bertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes StiftelseAvailable from: 2023-06-30 Created: 2023-06-30 Last updated: 2024-02-23Bibliographically approved
In thesis
1. A stargazer's guide to neurodegeneration: Astrocytes' role in the propagation of pathological proteins
Open this publication in new window or tab >>A stargazer's guide to neurodegeneration: Astrocytes' role in the propagation of pathological proteins
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of pathogenic protein aggregates. In the AD brain, amyloid-β (Aβ) and tau form plaques respective tangles, while in the PD brain α-synuclein (α-syn) form Lewy bodies and Lewy neurites. In addition, deposits of Aβ, tau and α-syn are frequently present in glial cells, including astrocytes. Historically, the focus was on neuronal dysfunction, leaving the involvement of glia largely understudied. The overall aim of this thesis was to investigate the role of glial cells in the disease progression, primarily focusing on astrocytes and the role they play in tau pathology.

Paper I focuses on the crosstalk between astrocytes and microglia in respects to degradation of α-syn and Aβ fibrils. Our results show that mono-cultured microglia are more effective than astrocytes at degrading exogenously added fibrils. However, when cultured together, microglia and astrocytes work synergistically, leading to an overall increase in the degradation.

In Paper II, we show that astrocytic tau inclusions are not benign, but in fact act as a reservoir for seeding competent tau species. The astrocytes engulf and process, but fail to fully degrade internalized material. Instead, seeding competent pathogenic tau spreads to nearby cells via secretion and tunneling nanotube mediated transfer. Furthermore, we show that tau and debris burdened astrocytes negatively affected the health of nearby neurons.

In Paper III, we investigated the cellular effects following astrocytic engulfment of human brain-derived tau. Our results show that astrocytes internalize and accumulate both AD and control tau fibrils. However, fibrils from AD brains were more neurotoxic and induced a stronger immune response in astrocytes, compared to fibrils derived from control brains.

In Paper IV, we studied the effects of APOE-genotype on astrocytic processing of tau by comparing astrocytes homozygous for APOEε2 and APOEε4. Our results showed that APOE2/2 astrocytes contained more and larger tau aggregates. Moreover, APOE 2/2 astrocytes excreted higher levels of pro-inflammatory cytokines, including IL-8, CCL2 and CXCL10 compared to APOE 4/4 astrocytes.

Paper V aimed to establish a cortical organoid model for studies of AD and PD. Exposure to α-syn especially led to internalisation by the organoid cells and active spreading throughout the tissue.

Our results demonstrate that astrocytes work closely with microglia to degrade internalised material. Furthermore, astrocytes actively contribute to neurodegeneration and disease propagation by affecting the health of neurons and by spreading seeding competent tau species.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 76
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2022
Keywords
Alzheimer’s disease, Parkinson’s disease, tauopathies, astrocyte, microglia, neuron, tau, amyloid-β, α-synuclein, accumulation, degradation, inflammation, spreading, seeding.
National Category
Medical and Health Sciences
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-523852 (URN)978-91-513-2045-8 (ISBN)
Public defence
2024-04-12, Rudbecksalen, Rudbeckslaboratoriet , Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2024-03-21 Created: 2024-02-23 Last updated: 2024-03-21

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Mothes, TobiasPortal, BenjaminKonstantinidis, EvangelosEltom, KhalidLibard, SylwiaStreubel-Gallasch, LinnIngelsson, MartinRostami, JinarLindskog, MariaErlandsson, Anna

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Mothes, TobiasPortal, BenjaminKonstantinidis, EvangelosEltom, KhalidLibard, SylwiaStreubel-Gallasch, LinnIngelsson, MartinRostami, JinarLindskog, MariaErlandsson, Anna
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