Single-molecule Observation of Self-Propagating Amyloid Fibrils.

Abstract

The assembly of misfolded proteins into amyloid fibrils is associated with amyloidosis, including neurodegenerative diseases, such as Alzheimer's, Parkinson's, and prion diseases. The self-propagation of amyloid fibrils is widely observed in the aggregation pathways of numerous amyloidogenic proteins. This propensity with plasticity in primary nucleation allows amyloid fibril polymorphism, which is correlated with the pathology/phenotypes of patients. Because the interference with the nucleation and replication processes of amyloid fibrils can alter the amyloid structure and the outcome of the disease, these processes can be a target for developing clinical drugs. Single-molecule observation of amyloid fibril replication can be an experimental system to provide the kinetic parameters for simulation studies and confirm the effect of clinical drugs. Here, we review single-molecule observation of the amyloid fibril replication process using fluorescence microscopy and time-lapse atomic force microscopy, including high-speed atomic force microscopy. We discussed the amyloid fibril replication process and combined single-molecule observation results with molecular dynamics simulations. Mini Abstract Structural dynamics in amyloid aggregation is related with various Alzheimer's and Parkinson's disease symptoms. Single-molecule observation using high-speed atomic force microscopy can directly visualize the structural dynamics of individual amyloid aggregate assemblies. Here, we review historical and recent studies of single-molecule observation of amyloid aggregation with supportive molecular dynamics simulation.