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Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0002-0270-2503
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.ORCID iD: 0000-0002-5817-9547
Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, BioClinicum, S-17164 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2023 (English)In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, article id 43Article in journal (Refereed) Published
Abstract [en]

Background: Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (A beta). However, in which way these A beta deposits influence their energy production remain unclear.

Methods: The aim of the present study was to investigate how A beta pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta(42) fibrils for 7 days and analyzed over time using different experimental approaches.

Results: Our results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the A beta-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the A beta-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid beta-oxidation and glycolysis.

Conclusions: Taken together, our data conclude that A beta pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023. Vol. 20, article id 43
Keywords [en]
Alzheimer's disease, Glia, Lipid droplets, Mitochondria dynamics, DRP-1
National Category
Neurology Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-498551DOI: 10.1186/s12974-023-02722-zISI: 000935963900001PubMedID: 36803838OAI: oai:DiVA.org:uu-498551DiVA, id: diva2:1744335
Funder
Swedish Research Council, 2021-02563Uppsala UniversityAlzheimerfonden, 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 Stiftelse
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2023-03-17 Created: 2023-03-17 Last updated: 2024-03-26Bibliographically 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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Zyśk, MarlenaBeretta, ChiaraDakhel, AbdulkhalekLindskog, MariaErlandsson, Anna

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