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:	Ching-Chia Huang, Kuo-Hsuan Chang, Ya-Jen Chiu, Yi-Ru Chen, Tsai-Hui Lung, Hsiu Mei Hsieh-Li, Ming-Tsan Su, Ying-Chieh Sun, Chiung-Mei Chen, Wenwei Lin, Guey-Jen Lee-Chen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Aβ Alzheimer’s disease coumarins TRKB agonist neuroprotection therapeutics Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/55f12e9aea6649f9b7d98415a9df3644
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spelling	oai:doaj.org-article:55f12e9aea6649f9b7d98415a9df36442021-11-25T17:11:26ZMulti-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity10.3390/cells101130952073-4409https://doaj.org/article/55f12e9aea6649f9b7d98415a9df36442021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3095https://doaj.org/toc/2073-4409Alzheimer’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.Ching-Chia HuangKuo-Hsuan ChangYa-Jen ChiuYi-Ru ChenTsai-Hui LungHsiu Mei Hsieh-LiMing-Tsan SuYing-Chieh SunChiung-Mei ChenWenwei LinGuey-Jen Lee-ChenMDPI AGarticleAβAlzheimer’s diseasecoumarinsTRKB agonistneuroprotectiontherapeuticsBiology (General)QH301-705.5ENCells, Vol 10, Iss 3095, p 3095 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aβ Alzheimer’s disease coumarins TRKB agonist neuroprotection therapeutics Biology (General) QH301-705.5
spellingShingle	Aβ Alzheimer’s disease coumarins TRKB agonist neuroprotection therapeutics Biology (General) QH301-705.5 Ching-Chia Huang Kuo-Hsuan Chang Ya-Jen Chiu Yi-Ru Chen Tsai-Hui Lung Hsiu Mei Hsieh-Li Ming-Tsan Su Ying-Chieh Sun Chiung-Mei Chen Wenwei Lin Guey-Jen Lee-Chen Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity
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.
format	article
author	Ching-Chia Huang Kuo-Hsuan Chang Ya-Jen Chiu Yi-Ru Chen Tsai-Hui Lung Hsiu Mei Hsieh-Li Ming-Tsan Su Ying-Chieh Sun Chiung-Mei Chen Wenwei Lin Guey-Jen Lee-Chen
author_facet	Ching-Chia Huang Kuo-Hsuan Chang Ya-Jen Chiu Yi-Ru Chen Tsai-Hui Lung Hsiu Mei Hsieh-Li Ming-Tsan Su Ying-Chieh Sun Chiung-Mei Chen Wenwei Lin Guey-Jen Lee-Chen
author_sort	Ching-Chia Huang
title	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_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_sort	multi-target effects of novel synthetic coumarin derivatives protecting aβ-gfp sh-sy5y cells against aβ toxicity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/55f12e9aea6649f9b7d98415a9df3644
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Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity

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