The p3 peptides (Aβ17-40/42) rapidly form amyloid fibrils that cross-seed with full-length Aβ

Yao Tian, Andrea P. Torres-Flores, Qi Shang, Hui Zhang, Anum Khursheed, Bogachan Tahirbegi, Patrick N. Pallier and John H. Viles ()
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Yao Tian: Queen Mary University of London
Andrea P. Torres-Flores: Queen Mary University of London
Qi Shang: Queen Mary University of London
Hui Zhang: Queen Mary University of London
Anum Khursheed: Queen Mary University of London
Bogachan Tahirbegi: Queen Mary University of London
Patrick N. Pallier: Queen Mary University of London
John H. Viles: Queen Mary University of London

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57341-4

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