Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism
Abstract 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 (Aβ). However,...
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02722-z |
| _version_ | 1797864015257403392 |
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| author | Marlena Zyśk Chiara Beretta Luana Naia Abdulkhalek Dakhel Linnea Påvénius Hjalmar Brismar Maria Lindskog Maria Ankarcrona Anna Erlandsson |
| author_facet | Marlena Zyśk Chiara Beretta Luana Naia Abdulkhalek Dakhel Linnea Påvénius Hjalmar Brismar Maria Lindskog Maria Ankarcrona Anna Erlandsson |
| author_sort | Marlena Zyśk |
| collection | DOAJ |
| description | Abstract 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 (Aβ). However, in which way these Aβ deposits influence their energy production remain unclear. Methods The aim of the present study was to investigate how Aβ 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 Aβ42 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 Aβ-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the Aβ-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 β-oxidation and glycolysis. Conclusions Taken together, our data conclude that Aβ pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression. |
| first_indexed | 2024-04-09T22:44:48Z |
| format | Article |
| id | doaj.art-6081aef51d4745efaada9dabbfba60ec |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-09T22:44:48Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-6081aef51d4745efaada9dabbfba60ec2023-03-22T11:55:03ZengBMCJournal of Neuroinflammation1742-20942023-02-0120111910.1186/s12974-023-02722-zAmyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolismMarlena Zyśk0Chiara Beretta1Luana Naia2Abdulkhalek Dakhel3Linnea Påvénius4Hjalmar Brismar5Maria Lindskog6Maria Ankarcrona7Anna Erlandsson8Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala UniversityDepartment of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala UniversityDepartment of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, BioClinicum, Karolinska InstitutetDepartment of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala UniversityScience for Life Laboratory, Department of Women’s and Children’s Health, Karolinska InstitutetScience for Life Laboratory, Department of Women’s and Children’s Health, Karolinska InstitutetDepartment of Medical Cell Biology, BMC, Uppsala UniversityDepartment of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, BioClinicum, Karolinska InstitutetDepartment of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala UniversityAbstract 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 (Aβ). However, in which way these Aβ deposits influence their energy production remain unclear. Methods The aim of the present study was to investigate how Aβ 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 Aβ42 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 Aβ-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the Aβ-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 β-oxidation and glycolysis. Conclusions Taken together, our data conclude that Aβ pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.https://doi.org/10.1186/s12974-023-02722-zAlzheimer’s diseaseGliaLipid dropletsMitochondria dynamicsDRP-1 |
| spellingShingle | Marlena Zyśk Chiara Beretta Luana Naia Abdulkhalek Dakhel Linnea Påvénius Hjalmar Brismar Maria Lindskog Maria Ankarcrona Anna Erlandsson Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism Journal of Neuroinflammation Alzheimer’s disease Glia Lipid droplets Mitochondria dynamics DRP-1 |
| title | Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism |
| title_full | Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism |
| title_fullStr | Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism |
| title_full_unstemmed | Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism |
| title_short | Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism |
| title_sort | amyloid β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism |
| topic | Alzheimer’s disease Glia Lipid droplets Mitochondria dynamics DRP-1 |
| url | https://doi.org/10.1186/s12974-023-02722-z |
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