Cross-Seeded Fibrillation Induced by Pyroglutamate-3 and Truncated Aβ<sub>40</sub> Variants Leads to Aβ<sub>40</sub> Structural Polymorphism Modulation and Elevated Toxicity
Zhiwen Hu, Letticia Cruceta, Shiyue Zhang, Yan Sun, Wei Qiang
Abstract
The pathological amyloid plaques in Alzheimer’s disease (AD) patients contain not only the wild-type β-amyloid (wt-Aβ) peptide sequences but also a variety of post-translationally modified variants. The pyroglutamate-3 Aβ (pyroE3-Aβ), which is generated from its truncated precursors ΔE3-Aβ, shows the highest abundance among all modified Aβ variants. Previous works have shown that pyroE3-Aβ and/or ΔE3-Aβ, compared with the wild-type sequences, led to a more rapid fibrillation process and final fibrils with higher neuronal cytotoxicity levels. However, much less is known about how the formation of pyroE3/ΔE3-Aβ fibrils would affect the amyloid deposition of wt-Aβ peptides, which are the main pathological events in AD. We show in the present work that the pyroE3/ΔE3-Aβ40 fibrils differ significantly from the wt-Aβ40 fibrils in terms of their molecular structures. When added into monomeric wt-Aβ40 peptides, these variant fibrils can cross-seed the formation of wt-Aβ40 fibrils with fibrillation kinetics that are greater than the self-seeded fibrillation of wt-Aβ40. Furthermore, the cross-seeding process modulates the molecular structures of the yielded wt-Aβ40 fibrils, which show similar features as their variant seeds. The cross-seeded fibrillation process also induces higher cytotoxicity levels compared with the self-seeded fibrillation of wt-Aβ40. Overall, our results support the hypothesis that pyroE3 and ΔE3-Aβ40 variants may serve as triggering factors of the pathological amyloid aggregation of wt-Aβ40 and may underlie the pathological significance of pyroE3/ΔE3-Aβ40 variants on the structural polymorphism of Aβ deposits.