Effects Of 8 Weeks Aerobic Exercise On Rho GTPases/cofilin Pathways In Cortex Of APP/PS1 Transgenic Mice

Objective:To investigate the effect of 8 weeks aerobic exercise on the cognitive-behavior and the Rho GTPasas/cofilin pathways in the cortex of 6-month-old APP/PS1 transgenic mouse.Methods:40 APP/PS1 transgenic mice (6-month-old) were randomly divided into 8 weeks exercise and sedentary respectively, namely APP/PS1 sedentary group (AS), APP/PS1 exercise(AE), and 20 C57BL/6J mice as the sedentary control group (CS). The exercised mice were subjected to a treadmill exercise protocol at the speed of 15m/min on an 0% slope for 10min/d then 18m/min for 50min/d. After exercise, the behavioral change was detected by step-down fear conditioning and rotarod test. Plasma corticosterone levels was quantified using a corticosterone EIA kit. The brains-were subjected to immunofluorescence and immunohistochemistry to analyze changes of Aβ. The levels of synaptophysin(Syn) in the prefrontal cortex and temporal lobe separately were detected with the ICH method, which has been widely used to assess synapse density. The protein levels of Syn and cofilin were measured using Western Blotting. We detected cofilin-actin rods by transmission electron microscopy(SEM). Furthermore,we detected the levels and activities of RhoA/Racl/Cdc42 with activition assay combo biochem kit.Results:l)Behaviorally, there was significant changes in 6-month-old AS compared with the control cohorts(CS)(P<0.05), the exercised mice performed significantly better than AS in both step-down fear conditioning and rotarod test(P<0.05).2)The basic levels of corticosterone had no significant difference between the groups, while after treadmill exercise the level was little increased.3) AP and cofilin was aggregated at cortex, while the synaptic density was decreased, especially at prefrontal cortex in AS compared with control cohorts(P<0.01). Furthermore, the cortical ultrastructure showed the granulovacuolar degeneration and the arrangement of microtubules and microfilament was disordered to induce likely cofilin-actin rod formation in AS.4)While after 8w aerobic exercise, the density and diameter of Aβ was significantly decreased in AE(P<0.05), and the expression of cofilin was significantly decreased in prefrontal cortex(P<0.01), and the level of Syn was increased. At the same time, the cellular structure disorder changes were ameliorated significantly.5) The expression of RhoA was increased, while Racl and Cdc42 was decreased significantly(P<0.05)in prefrontal cortex in 6-month-old APP/PS1 mice. After 8w aerobic exercise, the changes were ameliorated significantly. The activity of Cdc42 in prefrontal cortex was decreased in AS,while after 8w aerobic exercise Cdc42’s activity was increased significantly(P<0.05).Conclusion:Aerobic exercise may reduce the extent of Aβ deposition in cortex of 6-month-old APP/PS1 transgenic mice, thus resulting in inhibiting cofilin aggregation and synaptic loss, which suggest, to an extent aerobic exercise would reduce neuropathology, rescue brain structure under neuropathological conditions by up-regulating the activity of Cdc42. That may be an important molecular mechanism of exercise-induced learning and memory ability promoting.