Objective β-Amyloid (Aβ) peptides play an important role in cognition deficits, neuroinflammation, and apoptosis observed in Alzheimers disease (AD).Activation of cyclic AMP (cAMP) signaling enhances memory and inhibits inflammatory and apoptotic responses.However, it is not known whether inhibition of phosphodiesterase-4 (PDE4), a critical controller of intracellular cAMP concentrations, affects AD-associated neuroinflammatory and apoptotic responses and whether these responses contribute to deficits of memory mediated by cAMP signaling.Methods The water-maze and passive avoidance tests were used to test memory in rats infused with aggregated Aβ25-35 into bilateral CA1 subregions in the presence or absence of rolipram, a prototypical PDE4 inhibitor.Levels of inflammatory factors and apoptosis-related proteins were measured in the hippocampus of these rats after behavioral tests and confirmed with Aβ1-42 treatment.Results Rats microinfused with Aβ25-35 (10 μg/side) into CA1 displayed deficits in learning ability and memory, as evidenced by increases in escape latency during acquisition trials and decreases in exploratory activities in the probe trial in the water-maze task and 24-h retention in the passive avoidance test.The memory deficits were reversed by rolipram (0.1, 0.25, and 0.5 mg/kg/d, i.p.) in a dose-dependent manner.Interestingly, Aβ25-35-treated rats also displayed decreases in expression of phosphorylated cAMP response-element binding protein (pCREB) and Bcl-2, but increases in expression of NF-κB p65 and Bax in the hippocampus; these effects were also reversed by rolipram in a dose-dependent manner.Similar neurochemical results were observed by replacing Aβ25-35 with Aβ1-42, a full-length amyloid peptide that quickly forms toxic oligomers.Conclusions These results suggest that PDE4 inhibitors such as rolipram may reverse Aβ-induced memory deficits at least in part via the attenuation of neuronal inflammation and apoptosis mediated by cAMP/CREB signaling.PDE4 could be a target for treatment of memory loss associated with AD.