Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid
Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by abnormal metabolism of β-amyloid (Aβ) precursor proteins and neuronal apoptosis, ultimately leading to cognitive dysfunction. The pathogenesis of AD is complex, and current single-target therapies are not effective...
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Elsevier
2025-05-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725001132 |
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| author | Dongsheng Ji Jiahui Zhang Jihai Liang Zhi-Shu Huang Bing Shu Ding Li |
| author_facet | Dongsheng Ji Jiahui Zhang Jihai Liang Zhi-Shu Huang Bing Shu Ding Li |
| author_sort | Dongsheng Ji |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by abnormal metabolism of β-amyloid (Aβ) precursor proteins and neuronal apoptosis, ultimately leading to cognitive dysfunction. The pathogenesis of AD is complex, and current single-target therapies are not effective in preventing the rapid progression of AD, which highlights the urgent need for developing multi-target drugs. In this study, a series of compounds were synthesized through a multi-targeting ligand strategy. After extensive screening and evaluation, we found a lead compound B14, which showed excellent dual targeting ability for effectively alleviating neuronal apoptosis and oxidative stress damage of AD. In our molecular and cellular level experiments, B14 could target and stabilize the i-motif structure formed on the BCL-2 promoter to upregulate BCL-2 expression, which could also bind to Aβ and inhibit its deposition. In the Aβ1-42-induced cell model, B14 could maintain mitochondrial function and number, regulate intracellular reactive oxygen species (ROS) and Ca2+ metabolism disorders, and effectively reduce Aβ1-42-induced apoptosis. Further studies showed that B14 also exhibited good ability to cross the blood-brain barrier (BBB), which significantly improved learning memory and cognitive deficits, reduced brain Aβ plaques, alleviated inflammation and restored oxidative stress markers in APP/PS1 mice. Our findings provide an innovative strategy of dual targeting BCL-2 promoter i-motif for transcriptional regulation and Aβ aggregation synergistically for mitigating AD pathologies. B14 represents a promising multi-target lead compound with a good potential for further development for AD treatment. |
| format | Article |
| id | doaj-art-bec7c51071b64a29a17510386873ef29 |
| institution | OA Journals |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-bec7c51071b64a29a17510386873ef292025-08-20T02:12:03ZengElsevierRedox Biology2213-23172025-05-018210360010.1016/j.redox.2025.103600Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloidDongsheng Ji0Jiahui Zhang1Jihai Liang2Zhi-Shu Huang3Bing Shu4Ding Li5School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University, City, 132 Waihuan East Road, Guangzhou, 510006, PR ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University, City, 132 Waihuan East Road, Guangzhou, 510006, PR ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University, City, 132 Waihuan East Road, Guangzhou, 510006, PR ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University, City, 132 Waihuan East Road, Guangzhou, 510006, PR ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, PR ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University, City, 132 Waihuan East Road, Guangzhou, 510006, PR China; Corresponding author.Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by abnormal metabolism of β-amyloid (Aβ) precursor proteins and neuronal apoptosis, ultimately leading to cognitive dysfunction. The pathogenesis of AD is complex, and current single-target therapies are not effective in preventing the rapid progression of AD, which highlights the urgent need for developing multi-target drugs. In this study, a series of compounds were synthesized through a multi-targeting ligand strategy. After extensive screening and evaluation, we found a lead compound B14, which showed excellent dual targeting ability for effectively alleviating neuronal apoptosis and oxidative stress damage of AD. In our molecular and cellular level experiments, B14 could target and stabilize the i-motif structure formed on the BCL-2 promoter to upregulate BCL-2 expression, which could also bind to Aβ and inhibit its deposition. In the Aβ1-42-induced cell model, B14 could maintain mitochondrial function and number, regulate intracellular reactive oxygen species (ROS) and Ca2+ metabolism disorders, and effectively reduce Aβ1-42-induced apoptosis. Further studies showed that B14 also exhibited good ability to cross the blood-brain barrier (BBB), which significantly improved learning memory and cognitive deficits, reduced brain Aβ plaques, alleviated inflammation and restored oxidative stress markers in APP/PS1 mice. Our findings provide an innovative strategy of dual targeting BCL-2 promoter i-motif for transcriptional regulation and Aβ aggregation synergistically for mitigating AD pathologies. B14 represents a promising multi-target lead compound with a good potential for further development for AD treatment.http://www.sciencedirect.com/science/article/pii/S2213231725001132Alzheimer's diseaseBCL-2I-motifβ-amyloid (Aβ)Oxidative stressanti-Apoptosis |
| spellingShingle | Dongsheng Ji Jiahui Zhang Jihai Liang Zhi-Shu Huang Bing Shu Ding Li Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid Redox Biology Alzheimer's disease BCL-2 I-motif β-amyloid (Aβ) Oxidative stress anti-Apoptosis |
| title | Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid |
| title_full | Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid |
| title_fullStr | Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid |
| title_full_unstemmed | Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid |
| title_short | Efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of Alzheimer's disease through dual targeting BCL-2 gene promoter i-motif and β-amyloid |
| title_sort | efficient strategy for alleviating neuronal apoptosis and oxidative stress damage of alzheimer s disease through dual targeting bcl 2 gene promoter i motif and β amyloid |
| topic | Alzheimer's disease BCL-2 I-motif β-amyloid (Aβ) Oxidative stress anti-Apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725001132 |
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