Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Abstract

Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-β (Aβ) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between Aβ and other amyloid proteins.

Keywords: Alzheimer disease; amyloid; amyloid-beta (Aβ); cross-amyloid interaction; fibrillation; oligomer; oligomerization.

FIGURE 1.

A cross-amyloid network for the Aβ peptide. Red lines: amyloid proteins that enhance the risk of AD in mice models or in vivo. Green lines: amyloid proteins that decrease the progression of AD in mice models. Blue circles: amyloid proteins that promote Aβ fibrillation in vitro. Green circles: amyloid proteins that suppress Aβ fibrillation in vitro. Gray circles and lines: unknown. The details of the interactions on which the connections are based are discussed in the article for each protein.

FIGURE 2.

A probabilistic consistency-based multiple alignment of amyloid protein sequences calculated by the T-coffee web server. Consistencies range from poor (blue) to good (red). It is clear that both the N termini and the C termini of amyloid proteins display high probabilistic sequence consistency.