An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity
Abstract The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer’s disease (AD). Developing molecules that can modulate this assemb...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60978-w |
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| author | Qijia Wei Dangliang Liu Wencheng Xia Fengzhang Wang Lu Huang Jun Zhang Xiaoya Wang Zhongxin Xu Changdong He Wenzhe Li Xiaomeng Shi Chu Wang Yuan Liu Cong Liu Suwei Dong |
| author_facet | Qijia Wei Dangliang Liu Wencheng Xia Fengzhang Wang Lu Huang Jun Zhang Xiaoya Wang Zhongxin Xu Changdong He Wenzhe Li Xiaomeng Shi Chu Wang Yuan Liu Cong Liu Suwei Dong |
| author_sort | Qijia Wei |
| collection | DOAJ |
| description | Abstract The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer’s disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine (β-GalNAc)-modified Aβ9-21 promotes Aβ42 fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ9-21 coassembles with Aβ42, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ9-21 can alleviate the neurotoxicity of Aβ42 in neuronal cells and an AD male mouse model. These findings underscore the potential of glycopeptides in regulating amyloid aggregation and provide structural insights for designing molecules targeting amyloid-related pathologies. |
| format | Article |
| id | doaj-art-6b1f4eeaa6fd48e58ffe9effd8b04f0d |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6b1f4eeaa6fd48e58ffe9effd8b04f0d2025-08-20T03:45:35ZengNature PortfolioNature Communications2041-17232025-07-0116111610.1038/s41467-025-60978-wAn O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicityQijia Wei0Dangliang Liu1Wencheng Xia2Fengzhang Wang3Lu Huang4Jun Zhang5Xiaoya Wang6Zhongxin Xu7Changdong He8Wenzhe Li9Xiaomeng Shi10Chu Wang11Yuan Liu12Cong Liu13Suwei Dong14State Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityInterdisciplinary Research Center on Biology and Chemistry, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesCollege of Chemistry and Molecular Engineering, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityCollege of Chemistry and Molecular Engineering, Peking UniversityCollege of Chemistry and Molecular Engineering, Peking UniversityInterdisciplinary Research Center on Biology and Chemistry, State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesState Key Laboratory of Natural and Biomimetic Drugs, Peking UniversityAbstract The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer’s disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine (β-GalNAc)-modified Aβ9-21 promotes Aβ42 fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ9-21 coassembles with Aβ42, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ9-21 can alleviate the neurotoxicity of Aβ42 in neuronal cells and an AD male mouse model. These findings underscore the potential of glycopeptides in regulating amyloid aggregation and provide structural insights for designing molecules targeting amyloid-related pathologies.https://doi.org/10.1038/s41467-025-60978-w |
| spellingShingle | Qijia Wei Dangliang Liu Wencheng Xia Fengzhang Wang Lu Huang Jun Zhang Xiaoya Wang Zhongxin Xu Changdong He Wenzhe Li Xiaomeng Shi Chu Wang Yuan Liu Cong Liu Suwei Dong An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity Nature Communications |
| title | An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity |
| title_full | An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity |
| title_fullStr | An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity |
| title_full_unstemmed | An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity |
| title_short | An O-glycopeptide participates in the formation of distinct Aβ42 fibril structures and attenuates Aβ42 neurotoxicity |
| title_sort | o glycopeptide participates in the formation of distinct aβ42 fibril structures and attenuates aβ42 neurotoxicity |
| url | https://doi.org/10.1038/s41467-025-60978-w |
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