The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ
Abstract The p3 peptides, Aβ17-40/42, are a common alternative cleavage product of the amyloid precursor protein, and are found in diffuse amyloid deposits of Alzheimer’s and Down Syndrome brains. The p3 peptides have been mis-named ‘non-amyloidogenic’. Here we show p340/42 peptides rapidly form amy...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57341-4 |
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| author | Yao Tian Andrea P. Torres-Flores Qi Shang Hui Zhang Anum Khursheed Bogachan Tahirbegi Patrick N. Pallier John H. Viles |
| author_facet | Yao Tian Andrea P. Torres-Flores Qi Shang Hui Zhang Anum Khursheed Bogachan Tahirbegi Patrick N. Pallier John H. Viles |
| author_sort | Yao Tian |
| collection | DOAJ |
| description | Abstract The p3 peptides, Aβ17-40/42, are a common alternative cleavage product of the amyloid precursor protein, and are found in diffuse amyloid deposits of Alzheimer’s and Down Syndrome brains. The p3 peptides have been mis-named ‘non-amyloidogenic’. Here we show p340/42 peptides rapidly form amyloid fibrils, with kinetics dominated by secondary nucleation. Importantly, cross-seeding experiments, with full-length Aβ induces a strong nucleation between p3 and Aβ peptides. The cross-seeding interaction is highly specific, and occurs only when the C-terminal residues are matched. We have imaged membrane interactions with p3, and monitored Ca2+ influx and cell viability with p3 peptide. Together this data suggests the N-terminal residues influence, but are not essential for, membrane disruption. Single particle analysis of TEM images indicates p3 peptides can form ring-like annular oligomers. Patch-clamp electrophysiology, shows p342 oligomers are capable of forming large ion-channels across cellular membranes. A role for p3 peptides in disease pathology should be considered as p3 peptides are cytotoxic and cross-seed Aβ fibril formation in vitro. |
| format | Article |
| id | doaj-art-8d3d9d5834854a7fa6f80307cfe8df65 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-8d3d9d5834854a7fa6f80307cfe8df652025-08-20T03:04:34ZengNature PortfolioNature Communications2041-17232025-02-0116111310.1038/s41467-025-57341-4The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length AβYao Tian0Andrea P. Torres-Flores1Qi Shang2Hui Zhang3Anum Khursheed4Bogachan Tahirbegi5Patrick N. Pallier6John H. Viles7Department of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of LondonDepartment of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of LondonDepartment of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of LondonDepartment of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of LondonDepartment of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of LondonDepartment of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of LondonThe Blizard Institute, Centre for Neuroscience, Surgery and Trauma, Queen Mary University of LondonDepartment of Biochemistry, School of Biological and Behavioural Sciences, Queen Mary University of LondonAbstract The p3 peptides, Aβ17-40/42, are a common alternative cleavage product of the amyloid precursor protein, and are found in diffuse amyloid deposits of Alzheimer’s and Down Syndrome brains. The p3 peptides have been mis-named ‘non-amyloidogenic’. Here we show p340/42 peptides rapidly form amyloid fibrils, with kinetics dominated by secondary nucleation. Importantly, cross-seeding experiments, with full-length Aβ induces a strong nucleation between p3 and Aβ peptides. The cross-seeding interaction is highly specific, and occurs only when the C-terminal residues are matched. We have imaged membrane interactions with p3, and monitored Ca2+ influx and cell viability with p3 peptide. Together this data suggests the N-terminal residues influence, but are not essential for, membrane disruption. Single particle analysis of TEM images indicates p3 peptides can form ring-like annular oligomers. Patch-clamp electrophysiology, shows p342 oligomers are capable of forming large ion-channels across cellular membranes. A role for p3 peptides in disease pathology should be considered as p3 peptides are cytotoxic and cross-seed Aβ fibril formation in vitro.https://doi.org/10.1038/s41467-025-57341-4 |
| spellingShingle | Yao Tian Andrea P. Torres-Flores Qi Shang Hui Zhang Anum Khursheed Bogachan Tahirbegi Patrick N. Pallier John H. Viles The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ Nature Communications |
| title | The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ |
| title_full | The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ |
| title_fullStr | The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ |
| title_full_unstemmed | The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ |
| title_short | The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ |
| title_sort | p3 peptides aβ17 40 42 rapidly form amyloid fibrils that cross seed with full length aβ |
| url | https://doi.org/10.1038/s41467-025-57341-4 |
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