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Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin

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 potentiat...

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Autores principales: Chang, Lan, Cui, Wei, Yang, Yong, Xu, Shujun, Zhou, Wenhua, Fu, Hongjun, Hu, Shengquan, Mak, Shinghung, Hu, Juwei, Wang, Qin, Pui-Yan Ma, Victor, Chung-lit Choi, Tony, Dik-lung Ma, Edmond, Tao, Liang, Pang, Yuanping, Rowan, Michael J., Anwyl, Roger, Han, Yifan, Wang, Qinwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508546/
https://www.ncbi.nlm.nih.gov/pubmed/26194093
http://dx.doi.org/10.1038/srep10256
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author Chang, Lan
Cui, Wei
Yang, Yong
Xu, Shujun
Zhou, Wenhua
Fu, Hongjun
Hu, Shengquan
Mak, Shinghung
Hu, Juwei
Wang, Qin
Pui-Yan Ma, Victor
Chung-lit Choi, Tony
Dik-lung Ma, Edmond
Tao, Liang
Pang, Yuanping
Rowan, Michael J.
Anwyl, Roger
Han, Yifan
Wang, Qinwen
author_facet Chang, Lan
Cui, Wei
Yang, Yong
Xu, Shujun
Zhou, Wenhua
Fu, Hongjun
Hu, Shengquan
Mak, Shinghung
Hu, Juwei
Wang, Qin
Pui-Yan Ma, Victor
Chung-lit Choi, Tony
Dik-lung Ma, Edmond
Tao, Liang
Pang, Yuanping
Rowan, Michael J.
Anwyl, Roger
Han, Yifan
Wang, Qinwen
author_sort Chang, Lan
collection PubMed
description 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.
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spelling pubmed-45085462015-07-28 Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin Chang, Lan Cui, Wei Yang, Yong Xu, Shujun Zhou, Wenhua Fu, Hongjun Hu, Shengquan Mak, Shinghung Hu, Juwei Wang, Qin Pui-Yan Ma, Victor Chung-lit Choi, Tony Dik-lung Ma, Edmond Tao, Liang Pang, Yuanping Rowan, Michael J. Anwyl, Roger Han, Yifan Wang, Qinwen Sci Rep Article 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. Nature Publishing Group 2015-07-21 /pmc/articles/PMC4508546/ /pubmed/26194093 http://dx.doi.org/10.1038/srep10256 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Chang, Lan
Cui, Wei
Yang, Yong
Xu, Shujun
Zhou, Wenhua
Fu, Hongjun
Hu, Shengquan
Mak, Shinghung
Hu, Juwei
Wang, Qin
Pui-Yan Ma, Victor
Chung-lit Choi, Tony
Dik-lung Ma, Edmond
Tao, Liang
Pang, Yuanping
Rowan, Michael J.
Anwyl, Roger
Han, Yifan
Wang, Qinwen
Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin
title Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin
title_full Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin
title_fullStr Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin
title_full_unstemmed Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin
title_short Protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin
title_sort protection against β-amyloid-induced synaptic and memory impairments via altering β-amyloid assembly by bis(heptyl)-cognitin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508546/
https://www.ncbi.nlm.nih.gov/pubmed/26194093
http://dx.doi.org/10.1038/srep10256
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