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Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.ORCID iD: 0000-0002-5817-9547
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Department of Neuroinflammation, UCL Queen Square Institute of Neurology, 1 Wakefield Street, WC1N 1PJ London, United Kingdom of Great Britain and Northern Ireland.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.ORCID iD: 0000-0002-0270-2503
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2024 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 128, article id 103916Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.

Place, publisher, year, edition, pages
Elsevier, 2024. Vol. 128, article id 103916
Keywords [en]
Alzheimer's disease, Amyloid β, Astrocytes, Aggregate
National Category
Other Medical Sciences not elsewhere specified Other Biological Topics Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-525108DOI: 10.1016/j.mcn.2024.103916ISI: 001175074700001OAI: oai:DiVA.org:uu-525108DiVA, id: diva2:1845043
Part of project
The impact of astrocytes on Alzheimer’s disease progression, Swedish Research Council
Funder
Uppsala UniversitySwedish Research Council, 2021-02563Alzheimerfonden, AF-980656Åhlén-stiftelsen, 223037The Swedish Brain Foundation, FO2022-0083Stiftelsen 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: 2024-03-15 Created: 2024-03-15 Last updated: 2024-04-09Bibliographically approved
In thesis
1. Astrocytes in Alzheimer’s disease: Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.
Open this publication in new window or tab >>Astrocytes in Alzheimer’s disease: Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Astrocytes play a central role in brain homeostasis, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Yet, their exact role in amyloid-beta (Aβ) pathology and chronic neuroinflammation is unclear. The aim of this thesis was to elucidate the impact of astrocytes in AD progression. For this purpose, astrocytes in different culture set-ups were exposed to soluble Aβ aggregates. The astrocytes engulf and process, but fail to fully degrade the Aβ aggregates, which are instead stored as large intracellular deposits. In Paper I, we show that extracellular vesicles (EVs), secreted from the Aβ-containing cells induce synaptic loss, axonal swelling and vacuolization of primary neurons, which consequently leads to apoptosis. 

Astrocytes play a central role in the brain’s energy metabolism and we were therefore interested in how Aβ pathology affects their metabolism. In Paper II, we report that Aβ accumulation in astrocytes disrupts mitochondrial fission/fusion homeostasis, resulting in decreased mitochondrial respiration and altered glycolysis. Interestingly, the astrocytes switch to fatty acid β oxidation with the aid of peroxisomes to maintain stable energy production. 

Another important task is to understand how astrocytes modify the ingested Aβ.  In Paper III, we characterized the astrocytic Aβ inclusions by isolating them with magnetic beads. Our analysis showed that the astrocytes truncate and pack together the Aβ aggregates. Moreover, we found that astrocytes release specifically truncated forms of Aβ via different routes.

Astrocytes’ involvement in lipid metabolism and inflammation has recently gained much interest, but many questions remain about the connection between these processes. In Paper IV, we show that Aβ pathology causes lipid droplet (LD) accumulation in astrocytes. Moreover, we could show that astrocytes frequently transfer LDs to neighboring cells, both through direct cell-to-cell contacts and via secretion. Astrocytes have previously been reported to express major histocompatibility complex II (MHCII) and have the capacity to perform as professional antigen presenting cells. Interestingly, our results demonstrate that LDs contain MHCII, identifying a link between LDs and inflammation in astrocytes.

Taken together, this thesis contributes with important knowledge of the role of astrocytes in AD pathology. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 66
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2041
Keywords
Alzheimer’s disease, astrocytes, amyloid-beta, extracellular vesicles, mitochondria, lipid droplets, lipid metabolism, inflammation
National Category
Neurosciences
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-525110 (URN)978-91-513-2089-2 (ISBN)
Public defence
2024-05-17, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds Väg 20, Uppsala, 09:15 (English)
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Supervisors
Available from: 2024-04-25 Created: 2024-03-26 Last updated: 2024-04-25

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Beretta, ChiaraDakhel, AbdulkhalekZyśk, MarlenaSehlin, DagMichno, WojciechErlandsson, Anna

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