GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat model
Abstract Astrocytes are essential for maintaining neuronal health and regulating the brain’s inflammatory environment. In this study, we developed an adeno-associated viral vector (AAV9) designed to selectively overexpress glial cell line-derived neurotrophic factor (GDNF) in astrocytes, using the a...
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Nature Portfolio
2025-06-01
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| Online Access: | https://doi.org/10.1038/s41598-025-02881-4 |
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| author | Ana Abril Vidal Escobedo Facundo Peralta Gustavo Ramón Morel Martino Avallone Tomas Björklund Paula Cecilia Reggiani Joaquín Pardo |
| author_facet | Ana Abril Vidal Escobedo Facundo Peralta Gustavo Ramón Morel Martino Avallone Tomas Björklund Paula Cecilia Reggiani Joaquín Pardo |
| author_sort | Ana Abril Vidal Escobedo |
| collection | DOAJ |
| description | Abstract Astrocytes are essential for maintaining neuronal health and regulating the brain’s inflammatory environment. In this study, we developed an adeno-associated viral vector (AAV9) designed to selectively overexpress glial cell line-derived neurotrophic factor (GDNF) in astrocytes, using the astrocyte-specific GFAP promoter and TdTomato for transduction tracking. This approach yielded targeted GDNF expression in hippocampal astrocytes. Sholl analysis revealed that GDNF overexpression significantly enhanced astrocytic branching complexity and process length. Using the intracerebroventricular streptozotocin (STZ) model of neurodegeneration, we evaluated the impact of GDNF on astrocytic morphology, neuroinflammation, and hippocampal-dependent memory. Although GDNF prevented astrocytic process length reduction, it did not mitigate neuroinflammation, as evidenced by persistent microglial activation, nor did it improve deficits in the novel object recognition task. However, GDNF + STZ treated animals performed similarly as SHAM controls at exploring the goal sector at the Barnes Maze. These findings demonstrate the capacity of the AAV-GFAP-GDNF-TdTom construct to induce astrocytic branching and partially preserve memory function. They also underscore its partial therapeutic potential in a neuroinflammatory, metabolically compromised and neurodegenerative context. |
| format | Article |
| id | doaj-art-789e91f3fd9d43348d58829d3930a237 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-789e91f3fd9d43348d58829d3930a2372025-08-20T03:10:28ZengNature PortfolioScientific Reports2045-23222025-06-0115111610.1038/s41598-025-02881-4GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat modelAna Abril Vidal Escobedo0Facundo Peralta1Gustavo Ramón Morel2Martino Avallone3Tomas Björklund4Paula Cecilia Reggiani5Joaquín Pardo6Facultad de Ciencias Médicas, Instituto de Investigaciones Bioquímicas de La Plata “Profesor Doctor Rodolfo R. Brenner”, Universidad Nacional de La PlataFacultad de Ciencias Médicas, Instituto de Investigaciones Bioquímicas de La Plata “Profesor Doctor Rodolfo R. Brenner”, Universidad Nacional de La PlataFacultad de Ciencias Médicas, Instituto de Investigaciones Bioquímicas de La Plata “Profesor Doctor Rodolfo R. Brenner”, Universidad Nacional de La PlataMolecular Neuromodulation, Wallenberg Neuroscience Center, Lund UniversityMolecular Neuromodulation, Wallenberg Neuroscience Center, Lund UniversityFacultad de Ciencias Médicas, Instituto de Investigaciones Bioquímicas de La Plata “Profesor Doctor Rodolfo R. Brenner”, Universidad Nacional de La PlataFacultad de Ciencias Médicas, Instituto de Investigaciones Bioquímicas de La Plata “Profesor Doctor Rodolfo R. Brenner”, Universidad Nacional de La PlataAbstract Astrocytes are essential for maintaining neuronal health and regulating the brain’s inflammatory environment. In this study, we developed an adeno-associated viral vector (AAV9) designed to selectively overexpress glial cell line-derived neurotrophic factor (GDNF) in astrocytes, using the astrocyte-specific GFAP promoter and TdTomato for transduction tracking. This approach yielded targeted GDNF expression in hippocampal astrocytes. Sholl analysis revealed that GDNF overexpression significantly enhanced astrocytic branching complexity and process length. Using the intracerebroventricular streptozotocin (STZ) model of neurodegeneration, we evaluated the impact of GDNF on astrocytic morphology, neuroinflammation, and hippocampal-dependent memory. Although GDNF prevented astrocytic process length reduction, it did not mitigate neuroinflammation, as evidenced by persistent microglial activation, nor did it improve deficits in the novel object recognition task. However, GDNF + STZ treated animals performed similarly as SHAM controls at exploring the goal sector at the Barnes Maze. These findings demonstrate the capacity of the AAV-GFAP-GDNF-TdTom construct to induce astrocytic branching and partially preserve memory function. They also underscore its partial therapeutic potential in a neuroinflammatory, metabolically compromised and neurodegenerative context.https://doi.org/10.1038/s41598-025-02881-4AstrocytesGDNFHippocampusAAV9Neurodegeneration |
| spellingShingle | Ana Abril Vidal Escobedo Facundo Peralta Gustavo Ramón Morel Martino Avallone Tomas Björklund Paula Cecilia Reggiani Joaquín Pardo GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat model Scientific Reports Astrocytes GDNF Hippocampus AAV9 Neurodegeneration |
| title | GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat model |
| title_full | GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat model |
| title_fullStr | GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat model |
| title_full_unstemmed | GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat model |
| title_short | GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer’s rat model |
| title_sort | gdnf overexpression in astrocytes enhances branching and partially preserves hippocampal function in an alzheimer s rat model |
| topic | Astrocytes GDNF Hippocampus AAV9 Neurodegeneration |
| url | https://doi.org/10.1038/s41598-025-02881-4 |
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