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DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission and reducing neuronal loss

Authors: Wei Zhou1, Wen-wen Lian1, Rong Yan1, Hao Jia1, Lv-jie Xu1, Lin Wang1, Ai-lin Liu1,2,3, Guan-hua Du1,2,3
1 Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2 Beijing Key Laboratory of Drug Target Research and Drug Screening, Beijing 100050, China
3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China
Correspondence to: Wei Zhou: liuailin@imm.ac.cn, Ai-lin Liu: liuailin@imm.ac.cn, Guan-hua Du: dugh@imm.ac.cn,
DOI: 10.1038/s41401-019-0312-y
Received: 23 April 2019
Accepted: 30 September 2019
Advance online: 4 November 2019

Abstract

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 AKT 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-α, 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.
Keywords: DL0410; Alzheimer’s disease; cognitive deficits; long-term potentiation; synaptic transmission; neuronal loss; APP/PS1 transgenic mice

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