Fig. 4

LDN/OSU-0215111 efficacy at severe disease stage. a–e Results of behavioral battery (n = 34/21/28/32, respectively). Long-term compound treatment continued to prevent the development of agitation-like behavior (a) while maintaining improved cognition in Y-maze (b) recognition memory in the NORT (c) and spatial memory in Barnes maze (d, e) in rTg4510 mice. f Loss of PSD-95 in rTg4510 hippocampal postsynaptic densities was robust (n = 8/group); however, compound treatment continued to significantly reduce synaptodegeneration. g, h PFC tripartite-synapse integrity (n = 4/group). Similar to the hippocampus at 4 months, rTg4510 PFC postsynaptic densities exhibit decreased PSD-95 expression (g) and increased crude membrane EAAT2 expression (h). Compound treatment partially normalized both phenotypes. i Representative immunohistochemistry images of the hippocampus (n = 4/group). Cell nuclei were stained by DAPI (blue). Quantification (right) is percent change relative to control vehicles (dashed line). Neurodegeneration (as assessed by NeuN) was observed in CA1 and DG of rTg4510 vehicle mice; however, compound treatment significantly reduced neuronal loss. A similar pattern was observed for synaptic integrity (synaptophysin). rTg4510 mice exhibit increased GFAP and Iba1 in CA1, which was reduced and partially normalized by compound treatment. Scale bar = 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001