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Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity

Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived ne...

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Autores principales: Huang, Ching-Chia, Chang, Kuo-Hsuan, Chiu, Ya-Jen, Chen, Yi-Ru, Lung, Tsai-Hui, Hsieh-Li, Hsiu Mei, Su, Ming-Tsan, Sun, Ying-Chieh, Chen, Chiung-Mei, Lin, Wenwei, Lee-Chen, Guey-Jen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619673/
https://www.ncbi.nlm.nih.gov/pubmed/34831318
http://dx.doi.org/10.3390/cells10113095
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author Huang, Ching-Chia
Chang, Kuo-Hsuan
Chiu, Ya-Jen
Chen, Yi-Ru
Lung, Tsai-Hui
Hsieh-Li, Hsiu Mei
Su, Ming-Tsan
Sun, Ying-Chieh
Chen, Chiung-Mei
Lin, Wenwei
Lee-Chen, Guey-Jen
author_facet Huang, Ching-Chia
Chang, Kuo-Hsuan
Chiu, Ya-Jen
Chen, Yi-Ru
Lung, Tsai-Hui
Hsieh-Li, Hsiu Mei
Su, Ming-Tsan
Sun, Ying-Chieh
Chen, Chiung-Mei
Lin, Wenwei
Lee-Chen, Guey-Jen
author_sort Huang, Ching-Chia
collection PubMed
description Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms.
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spelling pubmed-86196732021-11-27 Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity Huang, Ching-Chia Chang, Kuo-Hsuan Chiu, Ya-Jen Chen, Yi-Ru Lung, Tsai-Hui Hsieh-Li, Hsiu Mei Su, Ming-Tsan Sun, Ying-Chieh Chen, Chiung-Mei Lin, Wenwei Lee-Chen, Guey-Jen Cells Article Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms. MDPI 2021-11-09 /pmc/articles/PMC8619673/ /pubmed/34831318 http://dx.doi.org/10.3390/cells10113095 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Huang, Ching-Chia
Chang, Kuo-Hsuan
Chiu, Ya-Jen
Chen, Yi-Ru
Lung, Tsai-Hui
Hsieh-Li, Hsiu Mei
Su, Ming-Tsan
Sun, Ying-Chieh
Chen, Chiung-Mei
Lin, Wenwei
Lee-Chen, Guey-Jen
Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
title Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
title_full Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
title_fullStr Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
title_full_unstemmed Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
title_short Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
title_sort multi-target effects of novel synthetic coumarin derivatives protecting aβ-gfp sh-sy5y cells against aβ toxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619673/
https://www.ncbi.nlm.nih.gov/pubmed/34831318
http://dx.doi.org/10.3390/cells10113095
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