Amyloid disorders cause debilitating illnesses through the formation of toxic protein aggregates. The mechanisms of amyloid toxicity and the nature of species responsible for mediating cellular dysfunction remain unclear. Here, using β 2 -microglobulin (β 2 m) as a model system, we show that the disruption of membranes by amyloid fibrils is caused by the molecular shedding of membrane-active oligomers in a process that is dependent on pH. Using thioflavin T (ThT) fluorescence, NMR, EM and fluorescence correlation spectroscopy (FCS), we show that fibril disassembly at pH 6.4 results in the formation of nonnative spherical oligomers that disrupt synthetic membranes. By contrast, fibril dissociation at pH 7.4 results in the formation of nontoxic, native monomers. Chemical cross-linking or interaction with hsp70 increases the kinetic stability of fibrils and decreases their capacity to cause membrane disruption and cellular dysfunction. The results demonstrate how pH can modulate the deleterious effects of preformed amyloid aggregates and suggest why endocytic trafficking through acidic compartments may be a key factor in amyloid disease.amyloid | fibrils | disassembly | oligomer | membrane disruption

including the URL of the record and the reason for the withdrawal request. Trends Box  Amyloid 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 their length distribution, thermodynamic stability, mechanical properties, and biological activity.  Amyloid fibres play a number of critical roles in disease, facilitating amyloid aggregate transmission, both between cells and, for prion-like species, between individuals.  Amyloid fibres 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.

Background: The causative agents and pathological mechanisms of amyloid disease are poorly understood.Results: β2-Microglobulin amyloid fibrils display length-dependent internalization, alter trafficking of lysosomal membrane proteins, and inhibit the degradation of proteins by lysosomes.Conclusion: Amyloid fibrils act as nanoparticles that disrupt membrane trafficking and protein degradation.Significance: Fibril length, by determining access to intracellular compartments, may contribute to amyloid disease.