Isoserine Improves Spatial Memory and Remodels Synaptic and Inflammatory Gene-Expression Programs in APP/PS1 Mice

Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer’s disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP/PS1 mice. Isoserine was well tolerated and did not adversely affect body weight. In the Morris water maze, isoserine improved probe-trial performance in APP/PS1 mice, significantly reducing latency to the first platform-location crossing, while time spent in the target quadrant showed a directionally consistent but non-significant increase. To identify molecular correlates, we profiled 84 synaptic-related genes using a targeted RT2 Profiler PCR Array. Gene-level factorial analyses identified several nominal treatment-associated effects, but no individual isoserine effect in APP/PS1 mice remained significant after false-discovery-rate correction. In contrast, module-level analyses identified False-discovery rate (FDR)-significant changes in NF-κB/inflammatory, synaptic-maintenance, and glutamatergic-signaling gene-expression modules, with significant genotype × treatment interactions for the NF-κB/inflammatory and synaptic-maintenance modules. Exploratory heatmap and principal component analyses further illustrated disease-context-dependent expression patterns. Western blot analyses showed that isoserine reduced nuclear factor kappa B (NF-κB p65) and NMDA receptor subunit GluN2B (GluN2B) and increased postsynaptic density protein 95 (PSD-95) levels in APP/PS1 mice. These findings suggest that isoserine improves spatial memory retention and coordinately remodels synaptic and inflammatory molecular programs in APP/PS1 mice.