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Bis(propyl)-cognitin Prevents β-amyloid-induced Memory Deficits as Well as Synaptic Formation and Plasticity Impairments via the Activation of PI3-K Pathway

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Abstract

Bis(propyl)-cognitin (B3C), derived from tacrine linked with three methylene (–CH2–) groups, is a dimerized molecule interacting multiple targets. During the past several years, it has been reported as a promising therapeutic drug for Alzheimer’s disease (AD) and other neurodegenerative disorders. However, the therapeutic mechanism of B3C for AD needs further demonstration. Based on a combination of behavioral tests, electrophysiological technique, immunocytochemistry, and live cell imaging, we studied the effects and the underlying mechanism of B3C on the impairments of cognitive function, synapse formation, and synaptic plasticity induced by soluble amyloid-β protein (Aβ) oligomers. Our study showed that spatial learning and memory in a Morris water maze task and recognition memory in a novel object recognition task were significantly decreased in the AD model mice created by hippocampal injection of Aβ. Chronic administration of B3C for 21 days prevented the memory impairments of the AD model mice in a dose-dependent manner. Live cell imaging study showed that 2-h pretreatment of B3C prevented the decrease in the number of filopodia and synapses induced by Aβ (0.5 μM) in a dose-dependent manner. Besides, electrophysiological recording data showed that the inhibition of long-term potentiation (LTP) induced by Aβ1–42 oligomers in the dentate gyrus (DG) of hippocampus was prevented by B3C in a dose-dependent manner. Furthermore, we found that the neuroprotective effect of B3C against Aβ-oligomer-induced impairments of synaptic formation and plasticity could be partially blocked by a specific phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 (50 μM). Therefore, these results indicate that B3C can prevent Aβ-oligomer-induced cognitive deficits, synaptic formation impairments, and synaptic plasticity impairments in a concentration-dependent manner. These effects of B3C are partially mediated via the PI3-K pathway. This study provides novel insights into the cellular mechanisms for the protective effects of B3C on AD.

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Acknowledgments

This work was supported by 973 Program from the Ministry of Science and Technology of China (2013CB835100), the National Natural Science Foundation of China (81471398, 30900430), Zhejiang Provincial Natural Science Foundation (LY14H090004), Ningbo Natural Science Foundation (No. 2014A610258), Program for Zhejiang Leading Team of S & T Innovation, P. R. China (No. 2011R50013-04), Ningbo Talent Project, Disciplinary Project of Ningbo University (NO. xkl141058), and K.C. Wong Magna Fund in Ningbo University.

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    Authors and Affiliations

    1. Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China

      Liting Jiang, Meng Huang, Shujun Xu, Yu Wang, Pengyuan An, Chenxi Feng, **aowei Chen, **aofei Wei & Qinwen Wang

    2. The First People’s Hospital of Yuhang District Hangzhou, 311100, Zhejiang, China

      Meng Huang

    3. Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China

      Yifan Han

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    Correspondence to Shujun Xu or Qinwen Wang.

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    Liting Jiang, Meng Huang and Shujun Xu contributed equally to this work.

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    Jiang, L., Huang, M., Xu, S. et al. Bis(propyl)-cognitin Prevents β-amyloid-induced Memory Deficits as Well as Synaptic Formation and Plasticity Impairments via the Activation of PI3-K Pathway. Mol Neurobiol 53, 3832–3841 (2016). https://doi.org/10.1007/s12035-015-9317-9

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