title: Bis(propyl)-cognitin Prevents β-amyloid-induced Memory Deficits as Well as Synaptic Formation and Plasticity Impairments via the Activation of PI3-K Pathway.
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.
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China.
authors.forename: Liting
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China.|The First People's Hospital of Yuhang District Hangzhou, 311100, Zhejiang, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China. xushujun@nbu.edu.cn.
authors.forename: Shujun
authors.initials: S
authors.lastname: Xu
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: An
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Feng
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 315211, Ningbo, China. wangqingwen@nbu.edu.cn.
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008813:Mice, Inbred ICR; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D055503:Protein Multimerization; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013619:Tacrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; C551529:bis(propyl)cognitin; D013619:Tacrine; D058539:Phosphatidylinositol 3-Kinase
keywords: Alzheimer’s disease; Aβ; Bis(propyl)-cognitin; Cognition; Learning; Memory; Phosphatidylinositol 3-kinase; Synapse formation; Synapse plasticity