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Objective Phosphodiseterase (PDE) is a superfamily of enzymes that catalyzes the hydrolysis of intracellular cAMP and/or cGMP.Among the 11 PDE families (PDE1-11), PDE4 is the most important family in the control of intracellular cAMP signaling.It has been well established that PDE4 plays an essential role in the mediation of memory.However, it is not known whether PDE4 is involved in memory associated with Alzheimers disease (AD).The objective of this study was to identify the role of PDE4 and its isoforms (PDE4A-D) in AD-related memory.Methods Mice deficient in PDE4A, PDE4B, or PDE4D were microinfused with β-amyloid peptide 1-42 (Aβ42; 0.4 μg/side) or vehicle into bilateral dorsal hippocampi before memory tests using the object recognition, passive avoidance, and Morris water-maze tasks.Gene silencing was used to identify the role of PDE4 variants in memory.Expression ofphosphorylated CREB (pCREB) in the hippocampus was also examined using Western blotting analysis.Results Mice deficient in PDE4A or PDE4D, but not PDE4B, displayed memory enhancement in one or all of the memory tests.PDE4A or PDE4D knockout mice also exhibited reversal of Aβ42-induced memory impairment, which was observed in wild-type mice in the object recognition, passive avoidance, and water-maze tests.Further, microinfusions of lentiviral vectors containing microRNAs (miRNAs) that target long-form PDE4D splice variants mimicked the ability of PDE4D deficiency to enhance memory in normal mice; the miRNAs also reversed Aβ42-induced memory deficits in the radial arm maze test in rats.Finally, Aβ42 decreased pCREB levels in the hippocampus of wild-type mice or negative control sequence-treated rats, but not mice deficient in PDE4A or PDE4D nor rats treated with PDE4D-miRNAs.Conclusion These results suggest that both PDE4A and PDE4D, in particular the long-form PDE4D isoforms, play an important role in the mediation of memory associated with Alzheimers disease.Targeting PDE4A or PDE4D may be a novel approach to treatment of disorders affecting memory and cognition.