Genetically-modified NSCs continue to produce neprilysin three months after unilateral transplantation and decrease Aβ load within the ipsilateral hippocampus of aged 3xTgAD mice. (A-C) Confocal microscopy reveals transplanted NSCs (green, GFP) within the alveus of the hippocampus (white matter tract overlying CA1) that secrete high levels of neprilysin (red) three months post-transplantation. (D-F) In contrast, control-transfected NSCs (green, GFP) show no detectable expression of neprilysin (red) in vivo. (G) High magnification of a sNEP-NSC-derived neuron shows high levels of sNEP (red) surrounding the engrafted cells. (H) Three months after transplantation, Aβ plaques (red, OC antibody) within the left side of the hippocampus (sNEP) are significantly reduced versus the contralateral hippocampus (Cntl). No obvious reduction in tau (blue, HT-7 antibody) is observed in aged animals, in line with prior findings that well-established insoluble NFTs are not decreased by Aβ-immunotherapy . Scale Bar = 45 μm in A-F, 15 μm in G, and 160 μm in H. Aβ, beta- amyloid; NFTs, neurofibrillary tangles; NSCs, neural stem cells; sNEP, secreted neprilysin.