title: Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin.
abstract: β-amyloid (Aβ) oligomers have been closely implicated in the pathogenesis of Alzheimer's disease (AD). We found, for the first time, that bis(heptyl)-cognitin, a novel dimeric acetylcholinesterase (AChE) inhibitor derived from tacrine, prevented Aβ oligomers-induced inhibition of long-term potentiation (LTP) at concentrations that did not interfere with normal LTP. Bis(heptyl)-cognitin also prevented Aβ oligomers-induced synaptotoxicity in primary hippocampal neurons. In contrast, tacrine and donepezil, typical AChE inhibitors, could not prevent synaptic impairments in these models, indicating that the modification of Aβ oligomers toxicity by bis(heptyl)-cognitin might be attributed to a mechanism other than AChE inhibition. Studies by using dot blotting, immunoblotting, circular dichroism spectroscopy, and transmission electron microscopy have shown that bis(heptyl)-cognitin altered Aβ assembly via directly inhibiting Aβ oligomers formation and reducing the amount of preformed Aβ oligomers. Molecular docking analysis further suggested that bis(heptyl)-cognitin presumably interacted with the hydrophobic pockets of Aβ, which confers stabilizing powers and assembly alteration effects on Aβ. Most importantly, bis(heptyl)-cognitin significantly reduced cognitive impairments induced by intra-hippocampal infusion of Aβ oligomers in mice. These results clearly demonstrated how dimeric agents prevent Aβ oligomers-induced synaptic and memory impairments, and offered a strong support for the beneficial therapeutic effects of bis(heptyl)-cognitin in the treatment of AD.
authors.affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Chang
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Shengquan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Shinghung
authors.initials: S
authors.lastname: Mak
authors.affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.
authors.forename: Juwei
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Victor Pui-Yan
authors.initials: VP
authors.lastname: Ma
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Tony Chung-lit
authors.initials: TC
authors.lastname: Choi
authors.affiliation: Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Edmond Dik-lung
authors.initials: ED
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
authors.affiliation: Mayo Foundation for Medical Education and Research, Rochester 55906-5425, MN, USA.
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Pang
authors.affiliation: Trinity College Institute of Neuroscience, Department of Pharmacology and Therapeutics, Department of Physiology.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
authors.affiliation: Trinity College Institute of Neuroscience, Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
authors.forename: Roger
authors.initials: R
authors.lastname: Anwyl
authors.affiliation: Department of Applied Biology and Chemistry Technology, Institute of Modern Chinese Medicine, the Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Physiology, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University. Ningbo 315211, China.
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004558:Electric Stimulation; D006624:Hippocampus / Q000473:pathology; D057927:Hydrophobic and Hydrophilic Interactions; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017433:Protein Structure, Secondary; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000473:pathology*; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D064569:alpha7 Nicotinic Acetylcholine Receptor; C000609450:bis(heptyl)cognitin; D013619:Tacrine