Lentiviral MiRNA-mediated PDE2 Knockdown Reverses Aβ42-induced Memory Impairment,Depression-and Anxiety-like Behaviors In Mice

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by progressive cognitive impairment and behavioral impairment,which is often accompanied by emotional disorder.To date,there are no treatments that cure or halt the progression of the AD and recent clinieal trials targeting acetylcholine,glutamate and even beta-amyloid(Aβ)plaque have not shown therapeutic effects on cognitive deficits.The pathogenesis of AD is not clear,it is generally believed that Aβ plays a key role.Emerging evidence suggests that Aβ has a detrimental effect on short-term and long-term memory,the initial and major symptom of AD,via inhibition of both cAMP/cGMP-dependent CREB pathway.Inhibition of phosphodiesterase(PDE)to increase cAMP/cGMP level my be an important approach for the treatment of Alzheimer’s disease.PDE inhibitors(PDEIs)are effective in the treatment of a variety of CNS diseases.Some PDEIs are not suitable for clinical development because of severe side effects.PDE2 is the most prevalent of PDEs expressed in the hippocampus and frontal cortex,regions involved in learning and memory and especially vulnerable to damage at early stages of AD.PDE2 inhibitor may be an ideal target for treatment of AD.However,PDE2 inhibitors available to date are not highly selective,which has limited the progress in studies identifying the CNS functions of PDE2Aims:1.To explore the feasibility of lentiviral miRNA-mediated PDE2Knockdown for the PDE2 functional research2.To Validate the effects of PDE2 in Aβ42-induced AD model and study the possible mechanismMethods:1.PDE2 lentivirus or cerebrospinal fluid(CSF)was injected into hippocampus CA1 area of mice.Transfection effect of PDE2 lentivirus was confirmed by immunofluorescence technique.The expression of PDE2 was measured by western blot.2.Aβ 42,PDE2 lentivirus or negtive control(NC)was injected into hippocampus CA1 area of mice.Memory ability,depression-and anxiety-like behaviors were measured through a series of behavioral experiments.Then the expression of PDE2,pCREB and BDNF were measured by western blotResults:1.GTP and DAPI fluorescence results showed that the virus vector was injected into the CA1 region of the mouse hippocampus and some of the hippocampus cells were transfected.Western blot results showed that PDE2 expression in PDE2miR group was significantly lower than vehicle group2.There was no significant difference of locomotor activity between each group.In Morris water maze and novel object recognization test,mouse in PDE2miR group had better memory ability than mouse in Aβ 42 group.In marble burying test and elevated plus maze,mouse in PDE2miR group acted less anxiety-like behavior than mouse in Aβ 42 group.In forced swimming test and tail suspension test,mouse in PDE2miR group acted less depression-like behavior than mouse in Aβ 42 group PDE2 expression of mouse in PDE2miR group was significantly lower than mouse in Aβ42 group.pCREB and BDNF expression of mouse in PDE2miR group was significantly higher than mouse in Aβ 42 groupConclusions:1.PDE2 lentivirus decreased PDE2 expression of mouse hippocampus.2.Lentiviral miRNA-mediated PDE2 knockdown reverses Aβ42-induced memory impairment,depression-and anxiety-like behaviors in mice.