“Development of a Viral Vector-Based Therapy Targeting Astrocytes in Alzheimer’s Disease”

Current therapeutic strategies for Alzheimer's Disease (AD) mainly target β-amyloid (Aβ) plaque reduction at advanced pathological stages. However, glial dysfunction appears before plaque formation, offering a window for an alternative therapy. Astrocytes express the metabotropic glutamate receptor mGlu3R, whose activation is neuroprotective: it promotes non-amyloidogenic APP cleavage, Aβ clearance, and neurotrophic factor release. We previously found that mGlu3R levels progressively decline in the hippocampus during pathological aging in AD mice (PDAPP-J20). Hence, restoring mGlu3R could recover these neuroprotective functions. We designed an adenoviral vector (AdV) expressing GRM3 (encoding mGlu3R) under the astrocyte-specific GFAP promoter, with GFP as reporter, and evaluated its cell selectivity, transduction efficiency, and safety. In vitro, astrocyte and microglia cultures/cell lines were transduced with AdV-0 (empty vector). Transduction rates for AdV-0 were 22% in primary astrocytes, 23.5% in U251 cells, and 0% in BV2 microglia. In vivo, C57BL6 mice received intrahippocampal injections of AdV-GRM3 or AdV-0. Over one month, no significant weight changes (p=0.81) or toxicity signs were observed. GFP expression confirmed vector localization within the hippocampus, without spreading to surrounding areas. These preliminary results show that AdV-GRM3 selectively and efficiently transduces astrocytes without evident toxicity, supporting future therapeutic evaluation.