Summary: Salt crystals can precipitate at low concentrations due to local density fluctuations. Their repeated precipitation dissolution behavior promotes amyloid-beta peptide aggregation.
Source: Osaka University
Alzheimer’s disease is the leading cause of dementia worldwide and a major cause of disability. Now, researchers at Osaka University and Hokkaido University have shown that repeated precipitation-dissolution events of salt crystals do occur even at low salt concentrations in nanoscales, and that it can accelerate the aggregation of the neurotoxic amyloid-β peptides implicated in its pathogenesis.
The human brain comprises around 86 billion neurons, roughly as many grains of sand as in a large dump truck. These neurons juggle electrochemical information as signals among the brain, muscles and organs to orchestrate the symphony of life from survival to self-awareness. Alzheimer’s disease disrupts this complex neuronal networking, causing functional disability and cell death. As yet uncurable, available treatments are symptomatic, supportive, or palliative; a breakthrough in understanding its pathogenesis may brighten the prospects for medication, diagnosis and prevention.
The role of amyloid in Alzheimer’s disease has long been recognized. Amyloid-β peptides are derived from amyloid precursor protein and they self-assemble into sizes ranging from low-molecular-weight aggregates and larger oligomers to amyloid fibrils. These last are known to be neurotoxic but recent research suggests that oligomeric disordered aggregates are also toxic, possibly even more than fibrils.
“Fibril aggregation begins with nucleation followed by an elongation stage,” explains Kichitaro Nakajima, lead author of this study. “Until now, the early stages of oligomer evolution have been difficult to study because of their morphologic variability, the timeframe for nucleation, and the lack of a suitable fluorescent assay.”
Using liquid-state transmission electron microscopy, the researchers analyzed the aggregation of protein molecules, acquiring time-resolved nanoscale images and electron diffraction patterns. “Remarkably, we discovered that a salt crystal can precipitate even at a concentration well below its solubility due to local density fluctuation, and its rapid dissolution accelerates the aggregation reaction of amyloid-β peptides,” says Professor Hirotsugu Ogi, the corresponding author. “This formation of temporary salt crystals provides a mechanism whereby proteins adhere to the surface of the crystal; as it dissolves, the interface shrinks, condensing the proteins at the vanishing point. This phenomenon resembles the aggregation acceleration by ultrasonic cavitation bubble. Proteins are attached on the bubble surface during the expansion phase, and they are highly condensed by the subsequent bubble collapses by the positive pressure of ultrasonic wave at its center. This is the artificial catalytic effect. Thus, in an autocatalytic-like nanoscopic aggregation mechanism, salt dissolution accelerates the aggregation reaction, and the aggregate itself can promote salt nucleation.”
Ogi explains the implications of their results: “The aggregation of amyloid-β peptides is slow and this has been a hindrance to pharmaceutical research. Establishing an effective acceleration method will help clarify their structural evolution from monomer to fibril. This knowledge is key to understanding the pathogenesis of Alzheimer’s disease.”
About this Alzheimer’s disease research article
Source: Osaka University Media Contacts: Saori Obayashi – Osaka University Image Source: The image is credited to Osaka University.
Time-resolved observation of evolution of amyloid-β oligomer with temporary salt crystals
The aggregation behavior of amyloid-β (Aβ) peptides remains unclarified despite the fact that it is closely related to the pathogenic mechanism of Alzheimer’s disease. Aβ peptides form diverse oligomers with various diameters before nucleation, making clarification of the mechanism involved a complex problem with conventional macroscopic analysis methods. Time-resolved single-molecule level analysis in bulk solution is thus required to fully understand their early stage aggregation behavior. Here, we perform time-resolved observation of the aggregation dynamics of Aβ oligomers in bulk solution using liquid-state transmission electron microscopy. Our observations reveal previously unknown behaviors. The most important discovery is that a salt crystal can precipitate even with a concentration much lower than its solubility, and it then dissolves in a short time, during which the aggregation reaction of Aβ peptides is significantly accelerated. These findings will provide new insights in the evolution of the Aβ oligomer.