Experiments on the International Space Station showed gravity affects the formation of amyloids, the pathological tangles of proteins found in the brains of those with Alzheimer’s disease.
Both the speed by which they formed and the structure they took in microgravity differed from amyloids formed through similar means in an Earth-bound lab, the scientists reported, helping to understand how proteins assemble in ways that turn toxic.
A study on this work, “Characterization of amyloid ß fibril formation under microgravity conditions,” was published in the journal npj Microgravity, a publication of the journal Nature.
Amyloid-beta is a peptide — a short chain of amino acids, the building blocks of proteins — found throughout the body. Although its normal healthy function remains a topic of debate, clumps of misfolded amyloid-beta in the brain area hallmark feature of Alzheimer’s disease and contribute to the death of neurons.
As such, amyloid-beta is an attractive target for potential Alzheimer’s therapies. But scientists have yet to understand how it converts from a soluble, single-molecule form to a pathological (disease-causing) clump of many misshapen molecules known as amyloid fibrils, or plaques.
Scientists know that amyloid-beta’s physiological environment influences amyloid formation. Picking apart each of the factors involved should reveal not only their role in fibril formation, but clues as to how they disrupt that process.
The effect of gravity is one key factor in any Earth-bound lab. Therefore, scientists from Japan sent four sets of frozen amyloid-beta samples to the Japanese Experiment Module, called KIBO, on the space station, where gravity is low enough to allow for weightlessness (microgravity). There they were incubated for nine days in conditions that would promote amyloid formation.
The samples then returned to Earth, where scientists compared the space-grown ones to Earth-grown samples incubated under the same conditions. That is, the only difference between the samples was gravity.
Samples grown in space showed a much slower rate of fibril formation than those that didn’t. Tests revealed that the amyloid-beta samples from the space station took longer to begin forming fibrils, and that this delay continued throughout the entire process. This suggested that microgravity affects the two phases of amyloid-beta self-organization: nucleation, in which a few individual proteins come together to form a fibril, and elongation, where these fibrils grow longer in size.
Amyloid fibril structures were then analyzed using cryogenic electron microscopy, a powerful technique in which electrons are used to reveal the shapes of individual molecules in cryogenically frozen samples. This is similar to how light is used to view shapes in conventional microscopy.
The space-grown fibrils were generally well separated and unbranched with periodic, or repeating, structures. They separated into two types, called type 1 and type 2. Type 1 fibrils, which accounted for roughly 80% of the total, had narrow crossovers, or points where the fibrils constricted, while type 2 crossovers were broader.
Although the ground-based fibrils, referred to as type G, bore more in common with type 1, both space-grown fibrils adopted generally more twisted structures than those of type G.
The researchers suggested that microgravity limits convective flow — that which is caused by different temperatures in a solution — through amyloid-beta’s natural environment. This, in turn, limits the number of times that growing fibrils come into contact with each other or with the bottom surface of petri dish, as would occur with gravity.
According to the researchers, the space station provides an ideal environment to study amyloid formation.
“The comparative analyses of amyloid fibril structures formed with and without gravity provide a deeper understanding of how microenvironmental factors surrounding assembling proteins affect fibril formation. Moreover, microgravity can offer unique opportunities for detailed observation of the earlier processes of amyloid formation,” they wrote.
In collaboration with other groups, the team intends to use this experimental setup to explore other variants of amyloid-beta, including hereditary ones, to understand the molecular mechanisms that drive amyloid formation and, more generally, the self-organization of biological molecules.
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