Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells
ABSTRACT Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuropr...
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| creator | Chi, Shun‐Tzu Wei, Pei‐Cih Chiu, Ya‐Jen Lin, Te‐Hsien Lin, Chih‐Hsin Chen, Chiung‐Mei Yao, Ching‐Fa Lin, Wenwei Lee‐Chen, Guey‐Jen Chang, Kuo‐Hsuan |
| description | ABSTRACT
Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling using SH‐SY5Y cells expressing Aβ‐green fluorescent protein (GFP) folding reporter. Among the tested compounds, two indole (NC009‐1, ‐6) and two coumarin (LM‐021, ‐036) derivatives effectively reduced Aβ misfolding and associated reactive oxygen species (ROS) production. Additionally, these compounds decreased acetylcholinesterase and caspase‐3/‐6 activities while promoting neurite outgrowth. NC009‐1 increased active phosphorylation of extracellular‐signal regulated kinase (ERK) (T202/Y204), leading to an increase in inactive eukaryotic elongation factor 2 kinase (EEF2K) phosphorylation (S366). LM‐021 decreased the active phosphorylation of AMP‐activated protein kinase (AMPK) (T172) and EEF2K (S398), while LM‐036 exhibited dual effects, increasing inactive phosphorylation and decreasing active phosphorylation of EEF2K. These changes in EEF2K phosphorylation led to decreased EEF2K activity and a subsequent reduction in inactive phosphorylation of EEF2 (T56). This cascade further promoted the phosphorylation of transcription factor cAMP‐response‐element binding protein (CREB) (S133) and the expression of brain‐derived neurotrophic factor (BDNF), and reduced BCL‐2 associated X‐protein (BAX)/B‐cell lymphoma 2 (BCL2) ratio. Knockdown of EEF2 abolished the effects of NC009‐1, LM‐021, and LM‐036 on CREB phosphorylation, BDNF expression, caspase‐3 activity, and neurite outgrowth. These findings demonstrate that NC009‐1, LM‐021, and LM‐036 exert their neuroprotective effects through modulation of EEF2K signaling, highlighting their potentials as therapeutic candidates for AD.
Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. In this study, we demonstrated the beneficial effects of indole (NC009‐1, NC009‐6) and coumarin (LM‐021, LM‐036) derivatives in ameliorating Aβ misfolding, reducing ROS production, caspase‐3/‐6 and acetylcholinesterase activity, as well as promoting neurite outgrowth. NC009‐ |
| doi_str_mv | 10.1111/jnc.16300 |
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Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling using SH‐SY5Y cells expressing Aβ‐green fluorescent protein (GFP) folding reporter. Among the tested compounds, two indole (NC009‐1, ‐6) and two coumarin (LM‐021, ‐036) derivatives effectively reduced Aβ misfolding and associated reactive oxygen species (ROS) production. Additionally, these compounds decreased acetylcholinesterase and caspase‐3/‐6 activities while promoting neurite outgrowth. NC009‐1 increased active phosphorylation of extracellular‐signal regulated kinase (ERK) (T202/Y204), leading to an increase in inactive eukaryotic elongation factor 2 kinase (EEF2K) phosphorylation (S366). LM‐021 decreased the active phosphorylation of AMP‐activated protein kinase (AMPK) (T172) and EEF2K (S398), while LM‐036 exhibited dual effects, increasing inactive phosphorylation and decreasing active phosphorylation of EEF2K. These changes in EEF2K phosphorylation led to decreased EEF2K activity and a subsequent reduction in inactive phosphorylation of EEF2 (T56). This cascade further promoted the phosphorylation of transcription factor cAMP‐response‐element binding protein (CREB) (S133) and the expression of brain‐derived neurotrophic factor (BDNF), and reduced BCL‐2 associated X‐protein (BAX)/B‐cell lymphoma 2 (BCL2) ratio. Knockdown of EEF2 abolished the effects of NC009‐1, LM‐021, and LM‐036 on CREB phosphorylation, BDNF expression, caspase‐3 activity, and neurite outgrowth. These findings demonstrate that NC009‐1, LM‐021, and LM‐036 exert their neuroprotective effects through modulation of EEF2K signaling, highlighting their potentials as therapeutic candidates for AD.
Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. In this study, we demonstrated the beneficial effects of indole (NC009‐1, NC009‐6) and coumarin (LM‐021, LM‐036) derivatives in ameliorating Aβ misfolding, reducing ROS production, caspase‐3/‐6 and acetylcholinesterase activity, as well as promoting neurite outgrowth. NC009‐1, LM‐021, and LM‐036 modulate EEF2 and EEF2K phosphorylation through the regulation of ERK and/or AMPK signaling pathways. These findings highlight the potential of these compounds as therapeutic candidates for AD.</description><identifier>ISSN: 0022-3042</identifier><identifier>ISSN: 1471-4159</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1111/jnc.16300</identifier><identifier>PMID: 39754378</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Acetylcholinesterase ; AD therapeutics ; Alzheimer's disease ; AMPK ; Axonogenesis ; Aβ cell model ; Bcl-2 protein ; Brain-derived neurotrophic factor ; Caspase ; Coumarin ; Cyclic AMP response element-binding protein ; EEF2K‐EEF2 ; Elongation ; ERK ; Fluorescence ; Folding ; Green fluorescent protein ; indole and coumarin derivatives ; Indoles ; Kinases ; Lymphoma ; Neurodegenerative diseases ; Neuromodulation ; Neuroprotection ; Phosphorylation ; Protein biosynthesis ; Protein folding ; Protein synthesis ; Proteins ; Reactive oxygen species ; β-Amyloid</subject><ispartof>Journal of neurochemistry, 2025-01, Vol.169 (1), p.e16300-n/a</ispartof><rights>2025 International Society for Neurochemistry.</rights><rights>Copyright © 2025 International Society for Neurochemistry</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2430-380087ad9f5d7be6e64488d58c89a0cbc523260e0b8dfa5627a2c40f17c4a50f3</cites><orcidid>0000-0003-4818-9917 ; 0000-0002-1107-772X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjnc.16300$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjnc.16300$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39754378$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chi, Shun‐Tzu</creatorcontrib><creatorcontrib>Wei, Pei‐Cih</creatorcontrib><creatorcontrib>Chiu, Ya‐Jen</creatorcontrib><creatorcontrib>Lin, Te‐Hsien</creatorcontrib><creatorcontrib>Lin, Chih‐Hsin</creatorcontrib><creatorcontrib>Chen, Chiung‐Mei</creatorcontrib><creatorcontrib>Yao, Ching‐Fa</creatorcontrib><creatorcontrib>Lin, Wenwei</creatorcontrib><creatorcontrib>Lee‐Chen, Guey‐Jen</creatorcontrib><creatorcontrib>Chang, Kuo‐Hsuan</creatorcontrib><title>Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>ABSTRACT
Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling using SH‐SY5Y cells expressing Aβ‐green fluorescent protein (GFP) folding reporter. Among the tested compounds, two indole (NC009‐1, ‐6) and two coumarin (LM‐021, ‐036) derivatives effectively reduced Aβ misfolding and associated reactive oxygen species (ROS) production. Additionally, these compounds decreased acetylcholinesterase and caspase‐3/‐6 activities while promoting neurite outgrowth. NC009‐1 increased active phosphorylation of extracellular‐signal regulated kinase (ERK) (T202/Y204), leading to an increase in inactive eukaryotic elongation factor 2 kinase (EEF2K) phosphorylation (S366). LM‐021 decreased the active phosphorylation of AMP‐activated protein kinase (AMPK) (T172) and EEF2K (S398), while LM‐036 exhibited dual effects, increasing inactive phosphorylation and decreasing active phosphorylation of EEF2K. These changes in EEF2K phosphorylation led to decreased EEF2K activity and a subsequent reduction in inactive phosphorylation of EEF2 (T56). This cascade further promoted the phosphorylation of transcription factor cAMP‐response‐element binding protein (CREB) (S133) and the expression of brain‐derived neurotrophic factor (BDNF), and reduced BCL‐2 associated X‐protein (BAX)/B‐cell lymphoma 2 (BCL2) ratio. Knockdown of EEF2 abolished the effects of NC009‐1, LM‐021, and LM‐036 on CREB phosphorylation, BDNF expression, caspase‐3 activity, and neurite outgrowth. These findings demonstrate that NC009‐1, LM‐021, and LM‐036 exert their neuroprotective effects through modulation of EEF2K signaling, highlighting their potentials as therapeutic candidates for AD.
Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. In this study, we demonstrated the beneficial effects of indole (NC009‐1, NC009‐6) and coumarin (LM‐021, LM‐036) derivatives in ameliorating Aβ misfolding, reducing ROS production, caspase‐3/‐6 and acetylcholinesterase activity, as well as promoting neurite outgrowth. NC009‐1, LM‐021, and LM‐036 modulate EEF2 and EEF2K phosphorylation through the regulation of ERK and/or AMPK signaling pathways. These findings highlight the potential of these compounds as therapeutic candidates for AD.</description><subject>Acetylcholinesterase</subject><subject>AD therapeutics</subject><subject>Alzheimer's disease</subject><subject>AMPK</subject><subject>Axonogenesis</subject><subject>Aβ cell model</subject><subject>Bcl-2 protein</subject><subject>Brain-derived neurotrophic factor</subject><subject>Caspase</subject><subject>Coumarin</subject><subject>Cyclic AMP response element-binding protein</subject><subject>EEF2K‐EEF2</subject><subject>Elongation</subject><subject>ERK</subject><subject>Fluorescence</subject><subject>Folding</subject><subject>Green fluorescent protein</subject><subject>indole and coumarin derivatives</subject><subject>Indoles</subject><subject>Kinases</subject><subject>Lymphoma</subject><subject>Neurodegenerative diseases</subject><subject>Neuromodulation</subject><subject>Neuroprotection</subject><subject>Phosphorylation</subject><subject>Protein biosynthesis</subject><subject>Protein folding</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>Reactive oxygen species</subject><subject>β-Amyloid</subject><issn>0022-3042</issn><issn>1471-4159</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNp1kM1Kw0AURgdRbK0ufAEJuNFF2jt_yWRZYqvVqiB1HSaTSUlJkzrTVPpaPojP5NRUF4J3c-Hew8fHQegcQx-7GSwq1ccBBThAXcxC7DPMo0PUBSDEp8BIB51YuwDAAQvwMerQKOSMhqKLHidVVpfak1XmxXWzlKaovBttio1cFxttvZk0c70uqrk3Go3Jg-few88Pb1yX2e74ole1WWvjxbos7Sk6ymVp9dl-99DreDSL7_zp8-0kHk59RRgFnwoAEcosynkWpjrQAWNCZFwoEUlQqeKEkgA0pCLLJQ9IKIlikONQMckhpz101eauTP3WaLtOloVVroGsdN3YhGKOueCYcode_kEXdWMq185RAQ4pIyRy1HVLKVNba3SerEzhZGwTDMnOceIcJ9-OHXuxT2zSpc5-yR-pDhi0wHtR6u3_Scn9U9xGfgFpcYN6</recordid><startdate>202501</startdate><enddate>202501</enddate><creator>Chi, Shun‐Tzu</creator><creator>Wei, Pei‐Cih</creator><creator>Chiu, Ya‐Jen</creator><creator>Lin, Te‐Hsien</creator><creator>Lin, Chih‐Hsin</creator><creator>Chen, Chiung‐Mei</creator><creator>Yao, Ching‐Fa</creator><creator>Lin, Wenwei</creator><creator>Lee‐Chen, Guey‐Jen</creator><creator>Chang, Kuo‐Hsuan</creator><general>Blackwell Publishing Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4818-9917</orcidid><orcidid>https://orcid.org/0000-0002-1107-772X</orcidid></search><sort><creationdate>202501</creationdate><title>Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells</title><author>Chi, Shun‐Tzu ; Wei, Pei‐Cih ; Chiu, Ya‐Jen ; Lin, Te‐Hsien ; Lin, Chih‐Hsin ; Chen, Chiung‐Mei ; Yao, Ching‐Fa ; Lin, Wenwei ; Lee‐Chen, Guey‐Jen ; Chang, Kuo‐Hsuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2430-380087ad9f5d7be6e64488d58c89a0cbc523260e0b8dfa5627a2c40f17c4a50f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Acetylcholinesterase</topic><topic>AD therapeutics</topic><topic>Alzheimer's disease</topic><topic>AMPK</topic><topic>Axonogenesis</topic><topic>Aβ cell model</topic><topic>Bcl-2 protein</topic><topic>Brain-derived neurotrophic factor</topic><topic>Caspase</topic><topic>Coumarin</topic><topic>Cyclic AMP response element-binding protein</topic><topic>EEF2K‐EEF2</topic><topic>Elongation</topic><topic>ERK</topic><topic>Fluorescence</topic><topic>Folding</topic><topic>Green fluorescent protein</topic><topic>indole and coumarin derivatives</topic><topic>Indoles</topic><topic>Kinases</topic><topic>Lymphoma</topic><topic>Neurodegenerative diseases</topic><topic>Neuromodulation</topic><topic>Neuroprotection</topic><topic>Phosphorylation</topic><topic>Protein biosynthesis</topic><topic>Protein folding</topic><topic>Protein synthesis</topic><topic>Proteins</topic><topic>Reactive oxygen species</topic><topic>β-Amyloid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chi, Shun‐Tzu</creatorcontrib><creatorcontrib>Wei, Pei‐Cih</creatorcontrib><creatorcontrib>Chiu, Ya‐Jen</creatorcontrib><creatorcontrib>Lin, Te‐Hsien</creatorcontrib><creatorcontrib>Lin, Chih‐Hsin</creatorcontrib><creatorcontrib>Chen, Chiung‐Mei</creatorcontrib><creatorcontrib>Yao, Ching‐Fa</creatorcontrib><creatorcontrib>Lin, Wenwei</creatorcontrib><creatorcontrib>Lee‐Chen, Guey‐Jen</creatorcontrib><creatorcontrib>Chang, Kuo‐Hsuan</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chi, Shun‐Tzu</au><au>Wei, Pei‐Cih</au><au>Chiu, Ya‐Jen</au><au>Lin, Te‐Hsien</au><au>Lin, Chih‐Hsin</au><au>Chen, Chiung‐Mei</au><au>Yao, Ching‐Fa</au><au>Lin, Wenwei</au><au>Lee‐Chen, Guey‐Jen</au><au>Chang, Kuo‐Hsuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>2025-01</date><risdate>2025</risdate><volume>169</volume><issue>1</issue><spage>e16300</spage><epage>n/a</epage><pages>e16300-n/a</pages><issn>0022-3042</issn><issn>1471-4159</issn><eissn>1471-4159</eissn><abstract>ABSTRACT
Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. This study investigated the neuroprotective effects of indole and coumarin derivatives on Aβ folding and EEF2 signaling using SH‐SY5Y cells expressing Aβ‐green fluorescent protein (GFP) folding reporter. Among the tested compounds, two indole (NC009‐1, ‐6) and two coumarin (LM‐021, ‐036) derivatives effectively reduced Aβ misfolding and associated reactive oxygen species (ROS) production. Additionally, these compounds decreased acetylcholinesterase and caspase‐3/‐6 activities while promoting neurite outgrowth. NC009‐1 increased active phosphorylation of extracellular‐signal regulated kinase (ERK) (T202/Y204), leading to an increase in inactive eukaryotic elongation factor 2 kinase (EEF2K) phosphorylation (S366). LM‐021 decreased the active phosphorylation of AMP‐activated protein kinase (AMPK) (T172) and EEF2K (S398), while LM‐036 exhibited dual effects, increasing inactive phosphorylation and decreasing active phosphorylation of EEF2K. These changes in EEF2K phosphorylation led to decreased EEF2K activity and a subsequent reduction in inactive phosphorylation of EEF2 (T56). This cascade further promoted the phosphorylation of transcription factor cAMP‐response‐element binding protein (CREB) (S133) and the expression of brain‐derived neurotrophic factor (BDNF), and reduced BCL‐2 associated X‐protein (BAX)/B‐cell lymphoma 2 (BCL2) ratio. Knockdown of EEF2 abolished the effects of NC009‐1, LM‐021, and LM‐036 on CREB phosphorylation, BDNF expression, caspase‐3 activity, and neurite outgrowth. These findings demonstrate that NC009‐1, LM‐021, and LM‐036 exert their neuroprotective effects through modulation of EEF2K signaling, highlighting their potentials as therapeutic candidates for AD.
Misfolding and accumulation of amyloid‐β (Aβ) in the brains of patients with Alzheimer's disease (AD) lead to neuronal loss through various mechanisms, including the downregulation of eukaryotic elongation factor 2 (EEF2) protein synthesis signaling. In this study, we demonstrated the beneficial effects of indole (NC009‐1, NC009‐6) and coumarin (LM‐021, LM‐036) derivatives in ameliorating Aβ misfolding, reducing ROS production, caspase‐3/‐6 and acetylcholinesterase activity, as well as promoting neurite outgrowth. NC009‐1, LM‐021, and LM‐036 modulate EEF2 and EEF2K phosphorylation through the regulation of ERK and/or AMPK signaling pathways. These findings highlight the potential of these compounds as therapeutic candidates for AD.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>39754378</pmid><doi>10.1111/jnc.16300</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-4818-9917</orcidid><orcidid>https://orcid.org/0000-0002-1107-772X</orcidid></addata></record> |
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| subjects | Acetylcholinesterase AD therapeutics Alzheimer's disease AMPK Axonogenesis Aβ cell model Bcl-2 protein Brain-derived neurotrophic factor Caspase Coumarin Cyclic AMP response element-binding protein EEF2K‐EEF2 Elongation ERK Fluorescence Folding Green fluorescent protein indole and coumarin derivatives Indoles Kinases Lymphoma Neurodegenerative diseases Neuromodulation Neuroprotection Phosphorylation Protein biosynthesis Protein folding Protein synthesis Proteins Reactive oxygen species β-Amyloid |
| title | Indole and Coumarin Derivatives Targeting EEF2K in Aβ Folding Reporter Cells |
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