Spatial Training Ameliorates Long-Term Alzheimer’s Disease-Like Pathological Deficits by Reducing NLRP3 Inflammasomes in PR5 Mice

Abstract

Recent studies have suggested that cognitive training could delay memory loss in Alzheimer's disease (AD). However, whether and how cognitive training produces long-term benefits remains unclear. Here, 10-month-old PR5 mice were spatially trained in a water maze for 4 consecutive weeks. The novel object recognition test (NORT), Western blots, Golgi staining, and ELISA were used to examine behavioral, biochemical, and pathological measures immediately after training and 3 months later. Immediately after training, we found that spatial training significantly improved cognitive performance; reduced tau neuropathology; increased the expression level of synaptophysin, PSD93, and PSD95 in the hippocampus; and increased the number of dendritic spines in PR5 mice. The expression levels of NLRP3, caspase-1, and interleukin (IL)-1β, which were significantly elevated in PR5 mice, were reversed by spatial training. Interestingly, these effects persisted 3 months later. To further detect the role of NLRP3 in spatial training, PR5/NLRP3−/− mice and PR5/NLRP3+/− mice were also used in our study. PR5/NLRP3−/− mice showed better cognitive performance than PR5 mice. After 1 week of spatial training, these changes (including those in expression levels of synaptophysin, PSD93, and PSD95; the number of dendritic spines; and caspase-1 and IL-1β content in PR5 mice) could be totally reversed in PR5/NLRP3−/− and PR5/NLRP3+/− mice. In addition, there was a positive correlation between NLRP3 content and the expression levels of caspase-1 and IL-1β. These results show an important role for the NLRP3/caspase-1/IL-1β axis in ameliorating the effect of spatial training on cognitive impairment in PR5 mice.

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