NT-3-Expressing Olfactory Ensheathing Cells Reduce Brain Aβ1-42 Accumulation and Improve Cognitive Performance in a Rat Model of Alzheimer's Disease.

Cell-based gene therapy is a promising strategy to promote regeneration in Alzheimer's disease (AD). Neurotrophin-3 (NT-3) plays a key role in neuroprotection and brain regeneration, providing a strong rationale for its exogenous delivery. Olfactory ensheathing cells (OECs) have high regenerative potential and serve as a vehicle for local gene delivery. We investigated the therapeutic potential of NT-3-expressing OECs in an Aβ1-42-induced AD model in female Wistar rats. Rat OECs were transduced with an Ad5RGD-CAG-NT-3 adenoviral vector, and NT-3 levels were measured in vitro using ELISA. To evaluate the efficacy of NT-3-transduced and non-transduced OECs, we performed behavioral assessments and measured the concentration of NT-3, Aβ1-42, and pTau levels in brain specimens 4 weeks post-transplantation. Transduced OECs exhibited markedly increased NT-3 secretion in vitro compared with non-transduced cells. All OEC-treated groups showed improved cognitive performance following transplantation. However, only NT-3-transduced OECs significantly increased brain NT-3 and reduced Aβ1-42 levels, indicating an enhanced therapeutic effect mediated by NT-3 overexpression. None of the cell grafts affected pTau levels. These findings demonstrate that OEC transplantation improves functional outcomes in experimental AD, while NT-3 overexpression provides biochemical benefits by reducing amyloid accumulation. Taken together, our findings support further investigation of NT-3-expressing OECs as a cell-based gene therapy for AD.