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OBJECTIVE Here we examined whether long form PDE4Ds reversed memory impairment produced by A β1-42(Aβ42).METHODS Morris water-maze and novelty object recognition tests were used for memory measurements.Western blotting analysis was used for determination of the expression of CREB, pCREB, BDNF, IL-1β, TNF-α and NF-κB in order to explore the neurochemical mechanisms.RESULTS Aged A β42(0.5 pg/side) infused in bilateral dentate gyri produced memory deficits in the Morris water-maze (P <0.0001) and object recog nition tests (P =0.0004) in mice.Microinfusions of lentiviral vectors containing miRNAs that target long-form PDF4D variants reversed A1β42-induced memory deficits and concomitandy in creased pCREB (P=0.0001) and BDNF (P <0.0001), and re duced inflammatory cytokines, including IL-1β (P =0.0026),TNF-a (P<0.0001), and NF-κB (P <0.0001) inthe hippo campus of Aβ42-treated mice.CCONCLUSION These results suggest that long-form PDE4D variants maybe potential targets for treatment of memory loss associated with Alzheimers disease.