ExCELLS utilizes the ISS microgravity environment to elucidate the fibrillar structure of amyloid β

The process of amyloid β (Aβ) self-assembly into fibrillar structures (fibrillization) holds the key to the onset of Alzheimer's disease (AD). Various structural forms of Aβ fibrils have been reported to date, but the elucidation of fibrillar structures of mutant Aβ related to familial Alzheimer's disease remains largely unresolved. The familial mutation known as the Tottori type involves the replacement of aspartic acid 7 (D7) with asparagine (N) at the N-terminal region of Aβ and is known to exhibit aggregation behavior different from normal Aβ. Under terrestrial conditions, this mutant form has difficulty forming well-structured amyloid fibrils and instead forms disordered amorphous aggregates, making structural analysis challenging using conventional methods.

A research group centered on Professor Koichi Kato of the Exploratory Research Center on Life and Living Systems (ExCELLS) at the National Institutes of Natural Sciences utilized the Japanese Experiment Module "Kibo" on the International Space Station to achieve the world's first successful fibril formation and structural analysis of the Tottori type (D7N mutation), which forms analytically intractable aggregates. Their results were published in ACS Chemical Neuroscience.

For the Tottori type Aβ40, which preferentially forms amorphous aggregates under terrestrial conditions, making structural analysis difficult, the microgravity environment suppressed amorphous aggregation and promoted efficient fibrillization. This enabled detailed structural analysis using cryo-electron microscopy.

The fibrillar structure obtained confirmed that the N-terminal region was flexible and did not adopt an ordered structure, suggesting that the D7N mutation eliminated the N-terminal stabilization mechanism of core structures observed in wild-type Aβ. This mutation is thought to promote amorphous aggregation and hinder fibrillization through changes in charge balance and increased hydrophobicity.

However, in the microgravity environment, convection and sedimentation caused by gravity were suppressed, limiting the occurrence of amorphous aggregation and enabling the formation of high-quality fibrils with converged structures.

This achievement not only provides new insights into elucidating the free energy landscape of Aβ fibril formation but is also expected to contribute to understanding the molecular mechanisms of familial Alzheimer's disease and developing future diagnostic and therapeutic targets.

Journal Information
Publication: ACS Chemical Neuroscience
Title: Microgravity-Assisted Exploration of the Conformational Space of Amyloid β Affected by Tottori-Type Familial Mutation D7N
DOI: 10.1021/acschemneuro.5c00217