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  • 1.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Astrocytes in Alzheimer’s disease: Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.2024Doctoral 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. 

    List of papers
    1. Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons
    Open this publication in new window or tab >>Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons
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    2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, article id 19656Article in journal (Refereed) Published
    Abstract [en]

    Alzheimer's disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-beta (A beta) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of A beta (42) protofibrils by astrocytes results in the release of EVs containing neurotoxic A beta. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and A beta (42) protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from A beta (42) protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from A beta exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of A beta -induced pathology.

    Place, publisher, year, edition, pages
    NATURE RESEARCH, 2020
    National Category
    Neurosciences
    Identifiers
    urn:nbn:se:uu:diva-428933 (URN)10.1038/s41598-020-72355-2 (DOI)000595255700049 ()33184307 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Brain FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla Tjänarinnor
    Available from: 2020-12-18 Created: 2020-12-18 Last updated: 2024-03-26Bibliographically approved
    2. Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism
    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
    3. Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms
    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
    4. 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
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  • 2.
    Beretta, Chiara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Eltom, Khalid
    Rosqvist, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Uzoni, Simon
    Department of Chemistry and Molecular Biology, University of Gothenburg.
    Mothes, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Rostami, Jinar
    Fletcher, John S.
    Department of Chemistry and Molecular Biology, University of Gothenburg.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Michno, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Astrocytes with Alzheimer’s disease pathology provoke lipid droplet mediated cell-to-cell propagation of MHC II complexesManuscript (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.

  • 3.
    Beretta, Chiara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nikitidou, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gallasch, Linn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, article id 19656Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-beta (A beta) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of A beta (42) protofibrils by astrocytes results in the release of EVs containing neurotoxic A beta. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and A beta (42) protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from A beta (42) protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from A beta exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of A beta -induced pathology.

    Download full text (pdf)
    FULLTEXT01
  • 4.
    Beretta, Chiara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Svensson, Elina
    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.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Zyśk, Marlena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Hanrieder, J.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Michno, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Molecular Geriatrics.
    Amyloid-β deposits in human astrocytes contain truncated and highly resistant proteoforms2024In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 128, article id 103916Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 5.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Long-term effects of amyloid-beta accumulation in human iPSC-derived astrocytesManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Alzheimer's disease (AD) is a slowly progressive condition and the most common cause of dementia worldwide. The pathological changes associated with the disease are estimated to occur decades before the first clinical symptoms emerge. Although neurons have been the main research focus, astrocytes have recently gained attention because of their participation in several key cellular functions. Our previous data suggest that astrocytes engulf large amounts of aggregated amyloid-beta (Aβ), but are unable to successfully degrade the material. The intracellular accumulation is, at least initially, very stressful for the astrocytes and long-term Aβ deposits may be detrimental for their functionality. However, if the astrocytes can handle the Aβ storage it could instead be beneficial in a longer perspective, by minimizing the spread of potentially pathogenic Aβ species to neighboring cells.

    Methods: We aimed to evaluate the effects of long-term Aβ inclusions in astrocytes. Mature human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils and then further cultured for one week or ten weeks in Aβ-free medium. Cells from both time points were analyzed for lysosomal proteins and astrocyte reactivity markers and the medium was screened for inflammatory cytokines. In addition, the overall health of cytoplasmic organelles was investigated by immunocytochemistry and electron microscopy.

    Results: Long-term astrocytes displayed frequent Aβ inclusions that were contained within LAMP1 positive organelles and sustained markers associated with reactivity. Furthermore, increased levels of CCL2/MCP-1 were detected in the media from Aβ-exposed long-term cultures. Finally, Aβ accumulation induced endoplasmic reticulum and mitochondrial swelling as well as formation of pathological lipid structures in astrocytes.

    Conclusions: This study provides valuable information about how intracellular Aβ deposits affect astrocytes over time, and thereby contribute to the understanding of astrocytes role in AD progression.

  • 6.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Long-term effects of amyloid-beta deposits in human iPSC-derived astrocytes2023In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 125, article id 103839Article in journal (Refereed)
    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.

    Download full text (pdf)
    fulltext
  • 7.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mothes, Tobias J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Amyloid-beta accumulation in astrocytes affects their impact on neuronal function in a human iPSC-based model of Alzheimer’s diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Although Alzheimer’s disease (AD) is the leading cause of dementia worldwide, there are currently no treatments available that limit the neurodegeneration or slow down the disease progression. Hence, innovative therapeutic approaches are clearly required. The role of astrocytes in AD has recently received much attention, due to their central function in brain homeostasis and synaptic function. Accumulating evidence indicates that astrocytes may lose the ability to fulfil some of their physiological tasks when shifting towards an inflammatory state. Our previous data demonstrate that astrocytes can ingest large amounts of aggregated amyloid-beta (Aβ), but then store, rather than degrade, the ingested material. This incomplete degradation results in severe cellular stress, which could be of relevance for AD progression.

    Methods: In this study, we aimed to investigate how inclusions of aggregated Aβ in astrocytes affect their interplay with neurons, focusing on cellular viability and synaptic function. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Αβ42 fibrils and their impact on hiPSC-derived neurons was analyzed by performing neuron-astrocyte co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures.

    Results: In the co-culture setup, the presence of Aβ inclusions led to an elevated clearance of dead cells by the astrocytes, indicating increased glial reactivity. In contrast, conditioned media from control, but not from Aβ-exposed astrocytes, benefited the wellbeing of neuronal monocultures. Furthermore, electrophysiological recordings showed a significant decrease in the frequency of excitatory post synaptic current (sEPSCs) in neurons co-cultured with Aβ-astrocytes compared to control astrocytes, while conditioned media from Aβ-exposed astrocytes had the opposite effect.

    Conclusions: Taken together, our results demonstrate that inclusions of aggregated Aβ affect the reactivity state of astrocytes, as well as their ability to support neuronal function.

  • 8.
    Konstantinidis, Evangelos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Portal, Benjamin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Mothes, Tobias J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Intracellular deposits of amyloid-beta influence the ability of human iPSC-derived astrocytes to support neuronal function2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, no 1, article id 3Article in journal (Refereed)
    Abstract [en]

    Background

    Astrocytes are crucial for maintaining brain homeostasis and synaptic function, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Our previous data demonstrate that astrocytes ingest large amounts of aggregated amyloid-beta (Aβ), but then store, rather than degrade the ingested material, which leads to severe cellular stress. However, the involvement of pathological astrocytes in AD-related synaptic dysfunction remains to be elucidated.

    Methods

    In this study, we aimed to investigate how intracellular deposits of Aβ in astrocytes affect their interplay with neurons, focusing on neuronal function and viability. For this purpose, human induced pluripotent stem cell (hiPSC)-derived astrocytes were exposed to sonicated Αβ42 fibrils. The direct and indirect effects of the Αβ-exposed astrocytes on hiPSC-derived neurons were analyzed by performing astrocyte–neuron co-cultures as well as additions of conditioned media or extracellular vesicles to pure neuronal cultures.

    Results

    Electrophysiological recordings revealed significantly decreased frequency of excitatory post-synaptic currents in neurons co-cultured with Aβ-exposed astrocytes, while conditioned media from Aβ-exposed astrocytes had the opposite effect and resulted in hyperactivation of the synapses. Clearly, factors secreted from control, but not from Aβ-exposed astrocytes, benefited the wellbeing of neuronal cultures. Moreover, reactive astrocytes with Aβ deposits led to an elevated clearance of dead cells in the co-cultures.

    Conclusions

    Taken together, our results demonstrate that inclusions of aggregated Aβ affect the reactive state of the astrocytes, as well as their ability to support neuronal function.

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  • 9.
    Rofo, Fadi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yilmaz, Canan Ugur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Metzendorf, Nicole G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gustavsson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nilsson, Per
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Enhanced neprilysin-mediated degradation of hippocampal A beta 42 with a somatostatin peptide that enters the brain2021In: Theranostics, E-ISSN 1838-7640, Vol. 11, no 2, p. 789-804Article in journal (Refereed)
    Abstract [en]

    Background: Aggregation of the amyloid-beta (A beta) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading A beta, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients. The poor delivery of SST over the blood-brain barrier (BBB) and its extremely short half-life of only 3 min limit its therapeutic significance.

    Methods: We recombinantly fused SST to a BBB transporter binding to the transferrin receptor. Using primary neuronal cultures and neuroblastoma cell lines, the ability of the formed fusion protein to activate neprilysin was studied. SST-scFv8D3 was administered to mice overexpressing the A beta-precursor protein (A beta PP) with the Swedish mutation (APPswe) as a single injection or as a course of three injections over a 72 h period. Levels of neprilysin and A beta were quantified using an Enzyme-linked immunosorbent assay (ELISA). Distribution of SST-scFv8D3 in the brain, blood and peripheral organs was studied by radiolabeling with iodine-125.

    Results: The construct, SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously and significantly increased the brain concentration of neprilysin in APPswe mice. A significant decrease in the levels of membrane-bound A beta 42 was detected in the hippocampus and the adjacent cortical area after only three injections.

    Conclusion: With intravenous injections of our BBB permeable SST peptide, we were able to significantly increase the levels neprilysin, an effect that was followed by a significant and selective degradation of membrane-bound A beta 42 in the hippocampus. Being that membrane-bound A beta triggers neuronal toxicity and the hippocampus is the central brain area in the progression of AD, the study has illuminated a new potential treatment paradigm with a promising safety profile targeting only the disease affected areas.

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  • 10.
    Streubel-Gallasch, Linn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zyśk, Marlena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 22982Article in journal (Refereed)
    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.

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  • 11.
    Zyśk, Marlena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beretta, Chiara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Naia, Luana
    Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, BioClinicum, S-17164 Stockholm, Sweden..
    Dakhel, Abdulkhalek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Pavenius, Linnea
    Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17165 Stockholm, Sweden..
    Brismar, Hjalmar
    Karolinska Inst, Dept Womens & Childrens Hlth, Sci Life Lab, S-17165 Stockholm, Sweden.;Royal Inst Technol, Dept Appl Phys, Sci Life Lab, S-17165 Stockholm, Sweden..
    Lindskog, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Research group Mia Lindskog.
    Ankarcrona, Maria
    Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc, BioClinicum, S-17164 Stockholm, Sweden..
    Erlandsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Amyloid-beta accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism2023In: Journal of Neuroinflammation, ISSN 1742-2094, E-ISSN 1742-2094, Vol. 20, article id 43Article in journal (Refereed)
    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.

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