Kinetics of amyloid accumulation in physiological viscosity

Abnormal aggregation and accumulation of misfolded proteins are involved in the development of various forms of amyloidosis. Aggregates that accumulate in organs induce an inflammatory response and cytotoxicity, and lead to organ failure. Although protein accumulation around an affected area in the body is an important stage that is directly linked to the mechanism of pathogenesis, the kinetics of the accumulation of protein that precipitates while assembling is not well understood because 3D tracking of proteins in solution is difficult. Here, we analyzed the process of aggregation and accumulation of amyloid β (Aβ), which causes the development of Alzheimer's disease (AD), by real-time 3D imaging under physiological conditions using a quantum dot nanoprobe that we previously developed. 3D observations demonstrated that Aβ aggregates with a diameter of several μm emerged in phosphate-buffered saline, gathered in a spiral-like step, and exhibited a mesh-like structure. Additionally, we found that the amount and size of aggregates decreased dramatically in 40% glycerol solution, mimicking the viscosity of human blood. We confirmed that fibrils in 40% glycerol exhibited an extremely short and tangled morphology and formed dense aggregates. Furthermore, numerical calculations revealed that several decades are required to fully develop the settling velocity and diameter of Aβ aggregates in physiological conditions. This time span is consistent with the actual symptom progression of AD. [Display omitted] •Quantum dots imaging revealed amyloid β aggregation and accumulation dynamics.•40% glycerol inhibited amyloid β aggregation and accumulation.•Transmission Electron Microscopy confirmed the aggregation of amyloid β.•Numerical calculations revealed amyloid β dynamics in physiological conditions.