Fang Zhang

Background: Phosphodiesterase 7 (PDE7) plays a role in neurological function. Increased expression and activity of PDE7 has been detected in several central nervous system diseases. However, the role of PDE7 in regulating stress levels remains unclear. Thus, this study aimed to determine whether and how PDE7 involved in the stress-induced behavioral and neuron morphological changes.Methods: The single prolonged stress (SPS) was used to build a stress exposure model in C57BL/6 J mice and detected PDE7 activity in hippocampus, amygdala, prefrontal cortex and striatum. Next, three doses (0.2, 1, and 5 mg/kg) of the PDE7 inhibitor BRL-50481 were intraperitoneally administered for 10 days, then behavioral, biochemical, and morphological tests were conducted.Results: PDE7 activity in hippocampus of mice significantly increased at all times after SPS. BRL-50481 significantly attenuated SPS induced anxiety-like behavior and fear response in both context and cue. In addition, BRL-50481 increased the levels of key molecules in the cAMP signaling pathway which were impaired by SPS. Immunofluorescent staining and Sholl analysis demonstrated that BRL-50481 also restored the nucleus/cytoplasm ratio of hippocampal neurons and improved neuronal plasticity. These effects of BRL-50481 were partially blocked by the TrkB inhibitor ANA-12.Conclusion: PDE7 inhibitors attenuate stress-induced behavioral changes by protecting the neuron cytoarchitecture and the neuronal plasticity in hippocampus, which is mediated at least partly through the activation of BDNF/TrkB signaling pathway. These results proved that PDE7 is a potential target for treating stress-induced behavioral and physiological abnormalities.

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer’s disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer’s disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits.