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

Abstract

In the amyloid plaques of Alzheimer’s disease (AD) patients, a large number of N-terminal-truncated amyloid β (Aβ) peptides such as Aβ11–40 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 Aβ11–40 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 Aβ11–40 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 Aβ11–40 seeds and induced β-sheet-rich fibrous aggregates of similar cytotoxicities for the two monomers. This indicates that Aβ40 and Aβ11–40 had similar aggregation pathways in the seeding and cross-seeding on Aβ40 seeds. By contrast, Aβ11–40 seeds led to different aggregation pathways of Aβ40 and Aβ11–40. Pure Aβ11–40 aggregates had higher toxicity than Aβ40 aggregates, and as seeds, Aβ11–40 seeds induced Aβ40 to form aggregates of higher cytotoxicity. However, homologous Aβ11–40 aggregates induced by Aβ11–40 seeds showed lower cytotoxicity than pure Aβ11–40 aggregates. The results suggest that Aβ11–40 plays an important role in the pathological process of AD.

Multistep changes in amyloid structure that are induced by cross-seeding on a rugged energy landscape

“…Whilst repeated self-seeding preserved each of these structural properties strictly (Figure 3), significant changes from the original structure imprinted by seed fibrils were observed through successive generations of cross-seeding. This observation was similar to structural deviations reported previously for prion (25,41) and other proteins (26,27) (Figure 4), demonstrating weak ability to preserve original seed structures in crossseeding.…”

The Aggregation Pattern of Aβ1–40 is Altered by the Presence of N‐Truncated Aβ4–40 and/or CuII in a Similar Way through Ionic Interactions

“…Very interestingly,t he addition of the Ntruncated Ab 11-40 peptider educed the lag time (t lag )o fA b 1-40 aggregation. [46,47] This is av ery interesting phenomenon, regardlesso ft he fact that Ab 11-40 is am inor brain speciesd ue to extensive cyclization of Glu11t oap yroGlu residue. [48] Similar behavior has also been reported for N-terminallye xtended peptides.…”

“…This feature is shared by other N ‐truncated peptides. Very interestingly, the addition of the N ‐truncated Aβ 11–40 peptide reduced the lag time ( t lag ) of Aβ 1–40 aggregation [46, 47] . This is a very interesting phenomenon, regardless of the fact that Aβ 11–40 is a minor brain species due to extensive cyclization of Glu11 to a pyroGlu residue [48] .…”

Effects of Aβ-derived peptide fragments on fibrillogenesis of Aβ

“…In addition, extensive somatic gene recombination in human neurons results in numerous APP variants with insertions, deletions, or missense mutations, including early termination codons and mutations linked to early onset AD 11 . In effect, the total Aβ pool in human brain is a heterogenous assembly of peptide species of different size and with distinct structural features and toxicities 12 – 17 .…”