Logo: to the web site of Uppsala University

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

Direct link
Dakhel, Abdulkhalek
Publications (4 of 4) 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
Konstantinidis, E., Dakhel, A., Beretta, C. & Erlandsson, A. (2023). Long-term effects of amyloid-beta deposits in human iPSC-derived astrocytes. Molecular and Cellular Neuroscience, 125, Article ID 103839.
Open this publication in new window or tab >>Long-term effects of amyloid-beta deposits in human iPSC-derived astrocytes
2023 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 125, article id 103839Article in journal (Refereed) Published
Abstract [en]

Growing evidence indicates that astrocytes are tightly connected to Alzheimer's disease (AD) pathogenesis. However, the way in which astrocytes participate in AD initiation and progression remains to be clarified. Our previous data show that astrocytes engulf large amounts of aggregated amyloid-beta (A beta) but are unable to successfully degrade the material. In this study, we aimed to evaluate how intracellular A beta-accumulation affects the astrocytes over time. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated A beta-fibrils and then cultured further for one week or ten weeks in A beta-free medium. Cells from both time points were analyzed for lysosomal proteins and astrocyte reactivity markers and the media were screened for inflammatory cytokines. In addition, the overall health of cytoplasmic organelles was investigated by immunocytochemistry and electron microscopy. Our data demonstrate that long-term astrocytes retained frequent A beta-inclusions that were enclosed within LAMP1-positive organelles and sustained markers associated with reactivity. Furthermore, A beta-accumulation resulted in endoplasmic reticulum and mitochondrial swelling, increased secretion of the cytokine CCL2/MCP-1 and formation of pathological lipid structures. Taken together, our results provide valuable information of how intracellular A beta-deposits affect astrocytes, and thereby contribute to the understanding of the role of astrocytes in AD progression.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Alzheimer?s disease, Amyloid beta, Astrocytes, Phagocytosis, Accumulation, Lysosomes, Neuroinflammation, Cytokines, Reactivity, Human iPSCs
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-500295 (URN)10.1016/j.mcn.2023.103839 (DOI)000957221400001 ()36907531 (PubMedID)
Funder
Swedish Research Council, 2021-02563
Available from: 2023-04-25 Created: 2023-04-25 Last updated: 2023-04-25Bibliographically approved
Beretta, C., Dakhel, A., Eltom, K., Rosqvist, F., Uzoni, S., Mothes, T., . . . Erlandsson, A.Astrocytes with Alzheimer’s disease pathology provoke lipid droplet mediated cell-to-cell propagation of MHC II complexes.
Open this publication in new window or tab >>Astrocytes with Alzheimer’s disease pathology provoke lipid droplet mediated cell-to-cell propagation of MHC II complexes
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background. Astrocytes are critical for maintaining brain homeostasis, but are also highly involved in neuroinflammation. In the Alzheimer disease (AD) brain, reactive, inflammatory astrocytes are situated closely around amyloid β (Aβ) plaques. We have previously shown that reactive astrocytes ingest large quantities of soluble Aβ aggregates, but are unable to degrade the material, which leads to intracellular Aβ accumulation and severe cellular stress. A common response to cellular stress is the formation of lipid droplets (LDs). Novel data indicate that LDs play an important role in inflammatory processes. However, the involvement of LDs in AD inflammation and progression remains unclear.

Methods. The aim of this study was to investigate how astrocytic Aβ pathology affects lipid metabolism and antigen presentation. For this purpose, human induced pluripotent stem cell (iPSC) derived astrocytes were exposed to soluble Aβ42 aggregates and analyzed over time, using a battery of experimental approaches.

Results. Our results show that Aβ exposure induces LD accumulation in astrocytes, although the overall lipid composition remains unchanged. Moreover, astrocytes transfer LDs to neighboring cells via tunneling nanotubes (TNTs) and extracellular vesicle (EVs). Interestingly, we found that the antigen presenting protein major histocompatibility complex II (MHCII) is present inside LDs, suggesting an active role of LDs in astrocytic antigen presentation. Immunohistochemical analysis of human brain tissue verified the presence of LD-loaded MHCII+ astrocytes in AD individuals. Moreover, we found infiltrated CD4+ T cells to be in close contact with astrocytes, confirming an astrocyte T cell cross-talk in the AD brain

Conclusions. Taken together, our data show that Aβ pathology drastically affects lipid storage in astrocytes, which in turn modulates the astrocytic antigen presentation, indicating a role for astrocytic LDs in T cell responses in the AD brain.

Keywords
Alzheimer’s disease, Aβ, astrocytes, lipid droplets, inflammation, MHCII, T cells
National Category
Neurosciences
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-525161 (URN)
Available from: 2024-03-26 Created: 2024-03-26 Last updated: 2024-03-26
Organisations

Search in DiVA

Show all publications