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Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.ORCID iD: 0000-0002-7427-9927
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.ORCID iD: 0009-0001-5223-0575
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Department of Pathology, Uppsala University Hospital, Sweden.ORCID iD: 0000-0003-1043-5385
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. University Health Network, Krembil Brain Institute, Toronto, Ontario, Canada. Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.ORCID iD: 0000-0001-5466-8370
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2024 (English)In: Acta neuropathologica communications, E-ISSN 2051-5960, Vol. 12, no 1, article id 34Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence highlights the involvement of astrocytes in Alzheimer’s disease (AD) progression. We have previously demonstrated that human iPSC-derived astrocytes ingest and modify synthetic tau fibrils in a way that enhances their seeding efficiency. However, synthetic tau fibrils differ significantly from in vivo formed fibrils. To mimic the situation in the brain, we here analyzed astrocytes’ processing of human brain-derived tau fibrils and its consequences for cellular physiology. Tau fibrils were extracted from both AD and control brains, aiming to examine any potential differences in astrocyte response depending on the origin of fibrils. Our results show that human astrocytes internalize, but fail to degrade, both AD and control tau fibrils. Instead, pathogenic, seeding capable tau proteoforms are spread to surrounding cells via tunneling nanotubes and exocytosis. Notably, accumulation of AD tau fibrils induces a stronger reactive state in astrocytes, compared to control fibrils, evident by the augmented expression of vimentin and GFAP, as well as by an increased secretion of the pro-inflammatory cytokines IL-8 and MCP-1. Moreover, conditioned media from astrocytes with AD tau fibril deposits induce synapse and metabolic impairment in human iPSC-derived neurons. Taken together, our data suggest that the accumulation of brain-derived AD tau fibrils induces a more robust inflammatory and neurotoxic phenotype in human astrocytes, accentuating the nature of tau fibrils as an important contributing factor to inflammation and neurodegeneration in AD. 

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024. Vol. 12, no 1, article id 34
Keywords [en]
Alzheimer’s disease; tau; astrocytes; brain-derived fibrils; inflammation; neurons
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-523823DOI: 10.1186/s40478-024-01745-8ISI: 001176894300001PubMedID: 38409026OAI: oai:DiVA.org:uu-523823DiVA, id: diva2:1840481
Part of project
The impact of astrocytes on Alzheimer’s disease progression, Swedish Research Council
Funder
Åhlén-stiftelsen, 233044The Swedish Brain Foundation, FO2022-0083Stiftelsen Gamla Tjänarinnor, 2021 − 01171O.E. och Edla Johanssons vetenskapliga stiftelseBertil and Ebon Norlin Foundation for Medical ResearchGun och Bertil Stohnes StiftelseSwedish Fund for Research Without Animal Experiments, F2022-0004Uppsala UniversityAvailable from: 2024-02-23 Created: 2024-02-23 Last updated: 2024-04-10Bibliographically 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)
Opponent
Supervisors
Available from: 2024-03-21 Created: 2024-02-23 Last updated: 2024-03-21

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Eltom, KhalidMothes, TobiasLibard, SylwiaIngelsson, MartinErlandsson, Anna

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