| Abstract: | AIM:To observe the effects of Rho kinase inhibitor fasudil on promoting nerve regeneration and improving cognitive function in amyloid precursor protein/presenilin 1 double transgenic (APP/PS1 Tg) mice, a widely used model of Alzheimer disease. METHODS:Male APP/PS1 Tg mice at 8 months old were randomly divided into 2 groups:the mice in fasudil group were intraperitoneally injected with fasudil at 25 mg/kg, while the mice in NS group were intraperitoneally injected with normal saline (NS), once daily for 2 months. Age-and sex-matched wild-type (WT) mice without treatment were used as controls. The Morris water maze (MWM) test and SMART 3.0 behavioral record system were applied to examine and analyze the spatial cognitive function of the mice. The protein levels and distribution of p-Tau, ChAT, BrdU and nestin in the hippocampal dentate gyrus (DG) and CA3 area and cerebral cortex were detected by immunohistochemistry. The protein levels of p-APP(Thr668) and p-Tau in the brain were analyzed by Western blot. RESULTS:Compared with control group, the APP/PS1 Tg mice (10 months old at the time of testing) treated with NS displayed the increase in the latency to target, and the decreases in the time and distance in SW (%) during the MWM test (SW was located in the area of the platform), indicating impaired cognition, which was reversed by fasudil treatment, indicating that the cognitive function was improved in the APP/PS1 Tg mice. In addition, compared with NS group, fasudil treatment significantly reduced the protein level of p-Tau, and increased the protein level of p-APP in the central nervous system (CNS) and the number of cholinergic neurons in the hippocampus. The neuronal axon regeneration in the hippocampus was promoted, and the endogenous neural stem cell proliferation in subgranular zone and subventricular zone of the hippocampal DG was also mobilized. CONCLUSION:Fasudil reverses spatial cognitive dysfunction in APP/PS1 Tg mice through decreasing the protein level of p-Tau, increasing the level of soluble APP, promoting the regeneration of cholinergic neurons, and mobilizating the endogenous neural stem cell proliferation in the CNS. |
