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  • 1.
    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.

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  • 2.
    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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  • 3.
    Zysk, Marlena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Clausen, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Aguilar, Ximena
    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.
    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 Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 72, no 1, p. 161-180Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12- and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-beta (A beta) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced A beta pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration.

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  • 4.
    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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