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

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.