Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Link to record
Permanent link

Direct link
Publications (3 of 3) Show all publications
Beretta, C., Svensson, E., Dakhel, A., Zyśk, M., Hanrieder, J., Sehlin, D., . . . Erlandsson, A. (2024). Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms. Molecular and Cellular Neuroscience, 128, Article ID 103916.
Open this publication in new window or tab >>Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms
Show others...
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
Keywords
Alzheimer's disease, Amyloid β, Astrocytes, Aggregate
National Category
Other Medical Sciences not elsewhere specified Other Biological Topics Neurosciences
Identifiers
urn:nbn:se:uu:diva-525108 (URN)10.1016/j.mcn.2024.103916 (DOI)001175074700001 ()
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 Stiftelse
Available from: 2024-03-15 Created: 2024-03-15 Last updated: 2024-04-09Bibliographically approved
Zyśk, M., Beretta, C., Naia, L., Dakhel, A., Pavenius, L., Brismar, H., . . . Erlandsson, A. (2023). Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism. Journal of Neuroinflammation, 20, Article ID 43.
Open this publication in new window or tab >>Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism
Show others...
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
Keywords
Alzheimer's disease, Glia, Lipid droplets, Mitochondria dynamics, DRP-1
National Category
Neurology Cell Biology
Identifiers
urn:nbn:se:uu:diva-498551 (URN)10.1186/s12974-023-02722-z (DOI)000935963900001 ()36803838 (PubMedID)
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
Streubel-Gallasch, L., Zyśk, M., Beretta, C. & Erlandsson, A. (2021). Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy. Scientific Reports, 11(1), Article ID 22982.
Open this publication in new window or tab >>Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy
2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 22982Article in journal (Refereed) Published
Abstract [en]

Traumatic brain injury (TBI) presents a widespread health problem in the elderly population. In addition to the acute injury, epidemiological studies have observed an increased probability and earlier onset of dementias in the elderly following TBI. However, the underlying mechanisms of the connection between TBI and Alzheimer’s disease in the aged brain and potential exacerbating factors is still evolving. The aim of this study was to investigate cellular injury-induced processes in the presence of amyloid β (Aβ) pathology. For this purpose, a co-culture system of cortical stem-cell derived astrocytes, neurons and oligodendrocytes were exposed to Aβ42 protofibrils prior to a mechanically induced scratch injury. Cellular responses, including neurodegeneration, glial activation and autophagy was assessed by immunoblotting, immunocytochemistry, ELISA and transmission electron microscopy. Our results demonstrate that the combined burden of Aβ exposure and experimental TBI causes a decline in the number of neurons, the differential expression of the key astrocytic markers glial fibrillary acidic protein and S100 calcium-binding protein beta, mitochondrial alterations and prevents the upregulation of autophagy. Our study provides valuable information about the impact of TBI sustained in the presence of Aβ deposits and helps to advance the understanding of geriatric TBI on the cellular level.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:uu:diva-461726 (URN)10.1038/s41598-021-02371-3 (DOI)000722925300054 ()34837024 (PubMedID)
Funder
Swedish Research Council
Available from: 2022-02-04 Created: 2022-02-04 Last updated: 2024-01-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0270-2503

Search in DiVA

Show all publications