Amyloid Fibres: Inert End-Stage Aggregates or Key Players in Disease?

The formation of amyloid fibres is a hallmark of amyloid disorders. Nevertheless, the lack of correlation between fibre load and disease as observed, for example, in Alzheimer's disease, means that fibres are considered secondary contributors to the onset of cellular dysfunction. Instead, soluble intermediates of amyloid assembly are often described as the agents of toxicity. Here, we discuss recent experimental discoveries which suggest that amyloid fibres should be considered as disease-relevant species that can mediate a range of pathological processes. These include disruption of biological membranes, secondary nucleation, amyloid aggregate transmission, and the disruption of protein homeostasis (proteostasis). Thus, a greater understanding of amyloid fibre biology could enhance prospects of developing therapeutic interventions against this devastating class of protein-misfolding disorders.

TrendsAmyloid fibres are proteinaceous filaments that form as a consequence of protein misfolding. Their formation is linked to over 50 human diseases, including Parkinson's and Alzheimer's diseases, and type 2 diabetes mellitus.Amyloid fibres are structurally polymorphic even when formed from the same sequence. The structure can alter fibre length distribution, thermodynamic stability, mechanical properties, and biological activity.Amyloid fibres have several critical roles in disease, facilitating amyloid aggregate transmission, both between cells and, for prion-like species, between individuals.Amyloid fibres can also sequester core components of the proteostasis network, disrupt membranes, and catalyse or cause the formation of cytotoxic oligomers.A comprehensive understanding of amyloid fibre biology will advance us towards our goal of therapeutic intervention.