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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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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. |
format | Online Article Text |
id | pubmed-4508546 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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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