At present,few available drugs can be used to either improve pathological features or prevent the progression of Alzheimer's disease (AD).DL0410 ((1,1'-([1,1'-biphenyl]-4,4'-diyl) bis (3-(piperidin-1-yl) propan-1-one) dihydrochloride) is a multiple-target small molecule that has been found to reverse cognitive impairment in different animal models of AD.In this study we evaluated the cognition-improving effects of DL0410 in APP/PS1 transgenic mice and explored the underlying mechanisms.APP/PS1 transgenic mice were administered DL0410 (3,10,30 mg.kg-1· d-1,ig) for 2 months.We found that DL0410 administration significantly ameliorated cognitive deficits in both the nest-building and Morris water maze tests.In electrophysiological analysis of hippocampal slices,we showed that DL0410 administration significantly enhanced the field EPSP slope and HFS-induced LTP in CA1 area.Furthermore,we revealed that DL0410 administration significantly increased the phosphorylation of AKr and the activity of GSK-3β in the hippocampus and cortex.Moreover,DL0410 administration dose-dependently increased the expression level of phosphorylated ERK1/2 in the hippocampus and cortex.In addition,DL0410 dose-dependently decreased the neuronal loss by decreasing the production of Aβ deposition,inhibited glial overactivation,and the production of inflammatory cytokines such as TNF-c,IL-1β,and IL-6.We conclude that DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission via activating the AKT/GSK-3β and MAPK/ERK signaling pathway and reducing neuronal loss.DL0410 may be an effective agent for AD treatment in the future.
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