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A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease

Ferroptosis, an iron-dependent cell death, plays a crucial role in the pathology of Alzheimer's disease (AD). Several characteristics of AD, including excessive iron accumulation, elevated lipid peroxide and reactive oxygen species (ROS) levels, and decreased glutathione peroxidase 4 (GPX4) lev...

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Autores principales: Baruah, Prayasee, Moorthy, Hariharan, Ramesh, Madhu, Padhi, Dikshaa, Govindaraju, Thimmaiah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10498722/
https://www.ncbi.nlm.nih.gov/pubmed/37712018
http://dx.doi.org/10.1039/d3sc02350h
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author Baruah, Prayasee
Moorthy, Hariharan
Ramesh, Madhu
Padhi, Dikshaa
Govindaraju, Thimmaiah
author_facet Baruah, Prayasee
Moorthy, Hariharan
Ramesh, Madhu
Padhi, Dikshaa
Govindaraju, Thimmaiah
author_sort Baruah, Prayasee
collection PubMed
description Ferroptosis, an iron-dependent cell death, plays a crucial role in the pathology of Alzheimer's disease (AD). Several characteristics of AD, including excessive iron accumulation, elevated lipid peroxide and reactive oxygen species (ROS) levels, and decreased glutathione peroxidase 4 (GPX4) levels, align with the features of ferroptosis. While traditional methods of inhibiting ferroptosis have centered on chelating Fe and trapping radicals, therapeutic strategies that modulate the GPX4 axis to mitigate ferroptosis in AD are yet to be explored. This report introduces naturally occurring polyphenols (PPs) as dual-acting therapeutic agents to synergistically alleviate ferroptosis and AD. The mechanisms of action encompass modulation of amyloid and tau cascade, reduction of oxidative stress, mitochondrial rescue, and inhibition of ferroptosis. For the first time, we show that a single multifunctional molecule, tannic acid (TA) binds at the activator site of GPX4, augmenting both its activity and cellular levels, providing a conceptually innovative and integrated approach for treating AD via the GPX4–ferroptosis axis. The ability of TA to enhance GPX4 levels under conditions of AD pathology opens up newer promising therapeutic avenues for combating the crosstalk between ferroptosis and AD.
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spelling pubmed-104987222023-09-14 A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease Baruah, Prayasee Moorthy, Hariharan Ramesh, Madhu Padhi, Dikshaa Govindaraju, Thimmaiah Chem Sci Chemistry Ferroptosis, an iron-dependent cell death, plays a crucial role in the pathology of Alzheimer's disease (AD). Several characteristics of AD, including excessive iron accumulation, elevated lipid peroxide and reactive oxygen species (ROS) levels, and decreased glutathione peroxidase 4 (GPX4) levels, align with the features of ferroptosis. While traditional methods of inhibiting ferroptosis have centered on chelating Fe and trapping radicals, therapeutic strategies that modulate the GPX4 axis to mitigate ferroptosis in AD are yet to be explored. This report introduces naturally occurring polyphenols (PPs) as dual-acting therapeutic agents to synergistically alleviate ferroptosis and AD. The mechanisms of action encompass modulation of amyloid and tau cascade, reduction of oxidative stress, mitochondrial rescue, and inhibition of ferroptosis. For the first time, we show that a single multifunctional molecule, tannic acid (TA) binds at the activator site of GPX4, augmenting both its activity and cellular levels, providing a conceptually innovative and integrated approach for treating AD via the GPX4–ferroptosis axis. The ability of TA to enhance GPX4 levels under conditions of AD pathology opens up newer promising therapeutic avenues for combating the crosstalk between ferroptosis and AD. The Royal Society of Chemistry 2023-08-22 /pmc/articles/PMC10498722/ /pubmed/37712018 http://dx.doi.org/10.1039/d3sc02350h Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Baruah, Prayasee
Moorthy, Hariharan
Ramesh, Madhu
Padhi, Dikshaa
Govindaraju, Thimmaiah
A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease
title A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease
title_full A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease
title_fullStr A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease
title_full_unstemmed A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease
title_short A natural polyphenol activates and enhances GPX4 to mitigate amyloid-β induced ferroptosis in Alzheimer's disease
title_sort natural polyphenol activates and enhances gpx4 to mitigate amyloid-β induced ferroptosis in alzheimer's disease
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10498722/
https://www.ncbi.nlm.nih.gov/pubmed/37712018
http://dx.doi.org/10.1039/d3sc02350h
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