Lenti‐GDNF Gene Therapy Protects Against Alzheimer's Disease‐Like Neuropathology in 3xTg‐AD Mice and MC65 Cells

Summary Aims Glial cell‐derived neurotrophic factor (GDNF) is emerging as a potent neurotrophic factor with therapeutic potential against a range of neurodegenerative conditions including Alzheimer's disease (AD). We assayed the effects of GDNF treatment in AD experimental models through gene‐therapy procedures. Methods Recombinant lentiviral vectors were used to overexpress GDNF gene in hippocampal astrocytes of 3xTg‐AD mice in vivo , and also in the MC65 human neuroblastoma that conditionally overexpresses the 99‐residue carboxyl‐terminal (C99) fragment of the amyloid precursor protein. Results After 6 months of overexpressing GDNF, 10‐month‐old 3xTg‐AD mice showed preserved learning and memory, while their counterparts transduced with a green fluorescent protein vector showed cognitive loss. GDNF therapy did not significantly reduce amyloid and tau pathology, but rather, induced a potent upregulation of brain‐derived neurotrophic factor that may act in concert with GDNF to protect neurons from atrophy and degeneration. MC65 cells overexpressing GDNF showed an abolishment of oxidative stress and cell death that was at least partially mediated by a reduced presence of intracellular C99 and derived amyloid β oligomers. Conclusions GDNF induced neuroprotection in the AD experimental models used. Lentiviral vectors engineered to overexpress GDNF showed to be safe and effective, both as a potential gene therapy and as a tool to uncover the mechanisms of GDNF neuroprotection, including cross talk between astrocytes and neurons in the injured brain.