An O-glycopeptide participates in the formation of distinct Aβ fibril structures and attenuates Aβ neurotoxicity.
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| Auteurs principaux: | , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Langue: | en |
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Nature communications
2025
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| _version_ | 1868266184089010177 |
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| author | Wei, Qijia Liu, Dangliang Xia, Wencheng Wang, Fengzhang Huang, Lu Zhang, Jun Wang, Xiaoya Xu, Zhongxin He, Changdong Li, Wenzhe Shi, Xiaomeng Wang, Chu Liu, Yuan Liu, Cong Dong, Suwei |
| author_facet | Wei, Qijia Liu, Dangliang Xia, Wencheng Wang, Fengzhang Huang, Lu Zhang, Jun Wang, Xiaoya Xu, Zhongxin He, Changdong Li, Wenzhe Shi, Xiaomeng Wang, Chu Liu, Yuan Liu, Cong Dong, Suwei Wei, Qijia Liu, Dangliang Xia, Wencheng Wang, Fengzhang Huang, Lu Zhang, Jun Wang, Xiaoya Xu, Zhongxin He, Changdong Li, Wenzhe Shi, Xiaomeng Wang, Chu Liu, Yuan Liu, Cong Dong, Suwei |
| collection | PubMed - marine biology |
| contents | An O-glycopeptide participates in the formation of distinct Aβ fibril structures and attenuates Aβ neurotoxicity. Wei, Qijia Liu, Dangliang Xia, Wencheng Wang, Fengzhang Huang, Lu Zhang, Jun Wang, Xiaoya Xu, Zhongxin He, Changdong Li, Wenzhe Shi, Xiaomeng Wang, Chu Liu, Yuan Liu, Cong Dong, Suwei Amyloid beta-Peptides Animals Glycopeptides Mice Peptide Fragments Molecular Dynamics Simulation Humans Alzheimer Disease Male Neurons Cryoelectron Microscopy Amyloid Disease Models, Animal Acetylgalactosamine Hydrophobic and Hydrophilic Interactions Protein Aggregation, Pathological 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 Aβ promotes Aβ fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ coassembles with Aβ, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ can alleviate the neurotoxicity of Aβ 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 | Artículo científico |
| id | pubmed_40593714 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Nature communications |
| record_format | pubmed |
| spellingShingle | An O-glycopeptide participates in the formation of distinct Aβ fibril structures and attenuates Aβ neurotoxicity. Wei, Qijia Liu, Dangliang Xia, Wencheng Wang, Fengzhang Huang, Lu Zhang, Jun Wang, Xiaoya Xu, Zhongxin He, Changdong Li, Wenzhe Shi, Xiaomeng Wang, Chu Liu, Yuan Liu, Cong Dong, Suwei Amyloid beta-Peptides Animals Glycopeptides Mice Peptide Fragments Molecular Dynamics Simulation Humans Alzheimer Disease Male Neurons Cryoelectron Microscopy Amyloid Disease Models, Animal Acetylgalactosamine Hydrophobic and Hydrophilic Interactions Protein Aggregation, Pathological An O-glycopeptide participates in the formation of distinct Aβ fibril structures and attenuates Aβ neurotoxicity. Wei, Qijia Liu, Dangliang Xia, Wencheng Wang, Fengzhang Huang, Lu Zhang, Jun Wang, Xiaoya Xu, Zhongxin He, Changdong Li, Wenzhe Shi, Xiaomeng Wang, Chu Liu, Yuan Liu, Cong Dong, Suwei Amyloid beta-Peptides Animals Glycopeptides Mice Peptide Fragments Molecular Dynamics Simulation Humans Alzheimer Disease Male Neurons Cryoelectron Microscopy Amyloid Disease Models, Animal Acetylgalactosamine Hydrophobic and Hydrophilic Interactions Protein Aggregation, Pathological 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 Aβ promotes Aβ fibrillation while reducing its toxic oligomers. Using biochemical assays, cryo-EM, and molecular dynamics simulations, we demonstrated that β-GalNAc-modified Aβ coassembles with Aβ, forming unique fibril structures stabilized by both hydrophobic interactions and an organized hydrogen bond network facilitated by the glycopeptide. Importantly, β-GalNAc-modified Aβ can alleviate the neurotoxicity of Aβ 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. |
| title | An O-glycopeptide participates in the formation of distinct Aβ fibril structures and attenuates Aβ neurotoxicity. |
| topic | Amyloid beta-Peptides Animals Glycopeptides Mice Peptide Fragments Molecular Dynamics Simulation Humans Alzheimer Disease Male Neurons Cryoelectron Microscopy Amyloid Disease Models, Animal Acetylgalactosamine Hydrophobic and Hydrophilic Interactions Protein Aggregation, Pathological |
| url | https://pubmed.ncbi.nlm.nih.gov/40593714/ |