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 inflammatoryenvironment. In this study, we developed an adeno-associated viral vector (AAV9) designed toselectively overexpress glial cell line-derived neurotrophic factor (GDNF) in astrocytes, usingthe astrocyte-specific GFAP promoter and TdTomato for transduction tracking. This approachyielded targeted GDNF expression in hippocampal astrocytes. Sholl analysis revealed that GDNFoverexpression significantly enhanced astrocytic branching complexity and process length. Using theintracerebroventricular streptozotocin (STZ) model of neurodegeneration, we evaluated the impact ofGDNF on astrocytic morphology, neuroinflammation, and hippocampal-dependent memory. AlthoughGDNF prevented astrocytic process length reduction, it did not mitigate neuroinflammation, asevidenced by persistent microglial activation, nor did it improve deficits in the novel object recognitiontask. However, GDNF + STZ treated animals performed similarly as SHAM controls at exploring thegoal sector at the Barnes Maze. These findings demonstrate the capacity of the AAV-GFAP-GDNFTdTomconstruct to induce astrocytic branching and partially preserve memory function. They alsounderscore its partial therapeutic potential in a neuroinflammatory, metabolically compromised andneurodegenerative context.