Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form of cell death plays a significant role in the multifaceted AD pathogenesis th...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-05-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231724000958 |
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| author | Dikshaa Padhi Prayasee Baruah Madhu Ramesh Hariharan Moorthy Thimmaiah Govindaraju |
| author_facet | Dikshaa Padhi Prayasee Baruah Madhu Ramesh Hariharan Moorthy Thimmaiah Govindaraju |
| author_sort | Dikshaa Padhi |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form of cell death plays a significant role in the multifaceted AD pathogenesis through generation of reactive oxygen species (ROS), mitochondrial damage, lipid peroxidation, and reduction in glutathione peroxidase 4 (GPX4) enzyme activity and levels. Aberrant liquid-liquid phase separation (LLPS) of tau drives the growth and maturation of NFTs contributing to AD pathogenesis. In this study, we strategically combined the structural and functional properties of gallic acid (GA) and cyclic dipeptides (CDPs) to synthesize hybrid molecules that effectively target both ferroptosis and amyloid toxicity in AD. This innovative approach marks a paradigm shift from conventional therapeutic strategies. This is the first report of a synthetic small molecule (GCTR) that effectively combats ferroptosis, simultaneously restoring enzymatic activity and enhancing cellular levels of its master regulator, GPX4. Further, GCTR disrupts Fe3+-induced LLPS of tau, and aids in attenuation of abnormal tau fibrillization. The synergistic action of GCTR in combating both ferroptosis and amyloid toxicity, bolstered by GPX4 enhancement and modulation of Fe3+-induced tau LLPS, holds promise for the development of small molecule-based novel therapeutics for AD. |
| first_indexed | 2024-04-24T16:50:05Z |
| format | Article |
| id | doaj.art-e2dca8e9fc66419da6c4decc71883f25 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-24T16:50:05Z |
| publishDate | 2024-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-e2dca8e9fc66419da6c4decc71883f252024-03-29T05:50:16ZengElsevierRedox Biology2213-23172024-05-0171103119Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's diseaseDikshaa Padhi0Prayasee Baruah1Madhu Ramesh2Hariharan Moorthy3Thimmaiah Govindaraju4Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, 560064, IndiaBioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, 560064, IndiaBioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, 560064, IndiaBioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, 560064, IndiaCorresponding author.; Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, 560064, IndiaAlzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form of cell death plays a significant role in the multifaceted AD pathogenesis through generation of reactive oxygen species (ROS), mitochondrial damage, lipid peroxidation, and reduction in glutathione peroxidase 4 (GPX4) enzyme activity and levels. Aberrant liquid-liquid phase separation (LLPS) of tau drives the growth and maturation of NFTs contributing to AD pathogenesis. In this study, we strategically combined the structural and functional properties of gallic acid (GA) and cyclic dipeptides (CDPs) to synthesize hybrid molecules that effectively target both ferroptosis and amyloid toxicity in AD. This innovative approach marks a paradigm shift from conventional therapeutic strategies. This is the first report of a synthetic small molecule (GCTR) that effectively combats ferroptosis, simultaneously restoring enzymatic activity and enhancing cellular levels of its master regulator, GPX4. Further, GCTR disrupts Fe3+-induced LLPS of tau, and aids in attenuation of abnormal tau fibrillization. The synergistic action of GCTR in combating both ferroptosis and amyloid toxicity, bolstered by GPX4 enhancement and modulation of Fe3+-induced tau LLPS, holds promise for the development of small molecule-based novel therapeutics for AD.http://www.sciencedirect.com/science/article/pii/S2213231724000958Alzheimer's diseaseFerroptosisGlutathione peroxidase 4Liquid-liquid phase separationHybrid molecules |
| spellingShingle | Dikshaa Padhi Prayasee Baruah Madhu Ramesh Hariharan Moorthy Thimmaiah Govindaraju Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease Redox Biology Alzheimer's disease Ferroptosis Glutathione peroxidase 4 Liquid-liquid phase separation Hybrid molecules |
| title | Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease |
| title_full | Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease |
| title_fullStr | Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease |
| title_full_unstemmed | Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease |
| title_short | Hybrid molecules synergistically mitigate ferroptosis and amyloid-associated toxicities in Alzheimer's disease |
| title_sort | hybrid molecules synergistically mitigate ferroptosis and amyloid associated toxicities in alzheimer s disease |
| topic | Alzheimer's disease Ferroptosis Glutathione peroxidase 4 Liquid-liquid phase separation Hybrid molecules |
| url | http://www.sciencedirect.com/science/article/pii/S2213231724000958 |
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