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GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer's rat model

Vidal Escobedo, Ana Abril ; Peralta, Facundo ; Morel, Gustavo Ramón ; Avallone, Martino LU ; Björklund, Tomas LU orcid ; Reggiani, Paula Cecilia and Pardo, Joaquin LU (2025) In Scientific Reports 15(1). p.1-16
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... (More)
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. (Less)
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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AAV9, Astrocytes, GDNF, Hippocampus, Neurodegeneration
in
Scientific Reports
volume
15
issue
1
article number
19284
pages
1 - 16
publisher
Nature Publishing Group
external identifiers
  • pmid:40456763
  • scopus:105007103716
ISSN
2045-2322
DOI
10.1038/s41598-025-02881-4
language
English
LU publication?
yes
id
d3e29de6-fedc-46f7-a413-ce903a73d0e6
date added to LUP
2025-06-10 17:39:36
date last changed
2025-07-14 10:58:01
@article{d3e29de6-fedc-46f7-a413-ce903a73d0e6,
  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.}},
  author       = {{Vidal Escobedo, Ana Abril and Peralta, Facundo and Morel, Gustavo Ramón and Avallone, Martino and Björklund, Tomas and Reggiani, Paula Cecilia and Pardo, Joaquin}},
  issn         = {{2045-2322}},
  keywords     = {{AAV9; Astrocytes; GDNF; Hippocampus; Neurodegeneration}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{1}},
  pages        = {{1--16}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{GDNF overexpression in astrocytes enhances branching and partially preserves hippocampal function in an Alzheimer's rat model}},
  url          = {{http://dx.doi.org/10.1038/s41598-025-02881-4}},
  doi          = {{10.1038/s41598-025-02881-4}},
  volume       = {{15}},
  year         = {{2025}},
}