The Phosphodiesterase-4 Inhibitor Roflumilast Reverses Cognition Deficits and Depression-Like Effects via cAMP Signaling-Mediated Neuroprotection in APP/PS1 Transgenic Mice

Background:Depression is highly correlated with Alzheimer's disease(AD),but treatment for the comorbidity of both is lacking. Phosphodiesterase-4(PDE4),an enzyme that catalyzes the hydrolysis of cyclic AMP(cAMP),has been considered as a promising target for treatment of both memory loss in AD and depression. Roflumilast,the second generation of PDE4 inhibitors,has been approved for treatment of chronic obstructive pulmonary disease(COPD) in humans. Recent studies have shown that roflumilast improves cognition at doses that do not cause an emetic response,the major side-effect of PDE4 inhibitors. However,the effect of roflumilast on memory loss and depression in AD remains largely unknown. Objective:To examine the effects of roflumilast on behavioral dysfunction and the related mechanisms in APP/PS1 double transgenic mice,a widely used model of AD. Methods:APP/PS1 mice and the wild type(WT) controls at 10 months of age were examined for memory using novel object recognition(NOR) and Morris water-maze(WMW) tests and depression using tail-suspension and forced-swimming tests(TST and FST). The protein contents were detected by Western blotting and Elisa kits. HE staining and Nissl staining were used to observe pathological changes. Results:Mice at 10 months of age were first tested in novel object recognition for memory. The recognition index in APP/PS1 mice was decreased compared to WT controls;this was reversed by roflumilast at 10 mg/kg. Similarly,in the Morris water-maze test,the AD mice displayed significantly longer escape latency during acquisition training and fewer entries into the target quadrant during the probe trial,compared to WT controls;these were also reversed by roflumilast at 5 and 10 mg/kg. In the tail-suspension and forced-swimming tests,which measure depression-like behavior,AD mice showed prolonged immobility time,which was reversed by roflumilast. In addition,the staining of HE and Nissl indicated that roflumilast reduced the loss of neurons and neurocyte apoptosis and reversed the decreased ratio of Bcl-2/Bax and the increased expression of PDE4 D in the cerebral cortex and hippocampus of AD mice. Finally,roflumilast reversed the decreases in the levels of cAMP,expression of phosphorylated cAMP response element-binding protein(CREB),and brain derived neurotrophic factor(BDNF) in AD mice. Conclusions:These results suggest that roflumilast not only improves learning and memory,but also attenuates depression-like behavior in AD mice,likely via PDE4 D/cAMP/CREB/BDNF signaling-mediated neuroprotection. Therefore,roflumilast can be a therapeutic agent for AD,in particular the comorbidity of memory deficits and depression.