Seeding and Cross-Seeding Aggregations of Aβ₄₀ and Its N-Terminal-Truncated Peptide Aβ_11-40

In the amyloid plaques of Alzheimer's disease (AD) patients, a large number of N-terminal-truncated amyloid β (Aβ) peptides such as Aβ_11-40 have been identified in addition to the full-length Aβ peptides. However, little is known about the roles of the N-terminal-truncated peptides in AD pathological process. Herein, seeding and cross-seeding aggregations of Aβ₄₀ and its N-terminal-truncated Aβ_11-40 were investigated in the solution and on the surfaces of chips with immobilized seeds by extensive biophysical and biological analyses. The results showed that Aβ₄₀ and Aβ_11-40 aggregates could seed both homologous and heterologous aggregations of the two monomers. However, the capability and characteristics of the seeding (homologous aggregation) and cross-seeding (heterologous aggregation) were significantly different. Aβ₄₀ seeds showed stronger acceleration effects on the aggregations than Aβ_11-40 seeds and induced β-sheet-rich fibrous aggregates of similar cytotoxicities for the two monomers. This indicates that Aβ₄₀ and Aβ_11-40 had similar aggregation pathways in the seeding and cross-seeding on Aβ₄₀ seeds. By contrast, Aβ_11-40 seeds led to different aggregation pathways of Aβ₄₀ and Aβ_11-40. Pure Aβ_11-40 aggregates had higher toxicity than Aβ₄₀ aggregates, and as seeds, Aβ_11-40 seeds induced Aβ₄₀ to form aggregates of higher cytotoxicity. However, homologous Aβ_11-40 aggregates induced by Aβ_11-40 seeds showed lower cytotoxicity than pure Aβ_11-40 aggregates. The results suggest that Aβ_11-40 plays an important role in the pathological process of AD.