Microgravity-Assisted Exploration of the Conformational Space of Amyloid β Affected by Tottori-Type Familial Mutation D7N
The amyloid β (Aβ) Tottori variant (D7N) exhibits unique aggregation behaviors and altered fibril formation, posing challenges for structural characterization. To overcome this, the microgravity environment on the International Space Station was employed to study Tottori-type Aβ40 fibril formation and structure. Under Earth gravity, Tottori-type Aβ40 primarily formed nonfibrillar aggregates, hindering detailed structural analysis. In contrast, microgravity significantly enhanced fibril formation and minimized amorphous aggregates. Cryo-electron microscopy revealed two structurally distinct fibril types, each comprising different protomer conformations. In both types, the N-terminal segment was disordered and nor resolved in the density maps. The D7N mutation disrupts the protection of the core by the N-terminal segment often observed in wild-type Aβ40 fibrils, enhancing the hydrophobicity-mediated aggregation propensity. However, microgravity suppressed kinetic traps and facilitated high-quality fibril formation suitable for structural studies that can explore the free energy landscape of Aβ fibril formation. These findings demonstrate the utility of microgravity for studying familial Aβ variants and potentially accelerate our understanding of Aβ aggregation mechanisms in Alzheimer's disease.
Authors
- Kazuyoshi Murata (ORCID: https://orcid.org/0000-0001-9446-3652)
- Raymond N. Burton‐Smith (ORCID: https://orcid.org/0000-0002-1535-6419)
- Chiaki Yamazaki
- Maho Yagi‐Utsumi (ORCID: https://orcid.org/0000-0001-8144-740X)
- Chihong Song (ORCID: https://orcid.org/0000-0001-8628-4267)
- Koichi Kato (ORCID: https://orcid.org/0000-0001-7187-9612)
- Toru Shimazu (ORCID: https://orcid.org/0000-0003-0343-8035)
- Christian Ganser (ORCID: https://orcid.org/0000-0002-5558-3026)
- Takayuki Uchihashi (ORCID: https://orcid.org/0000-0002-0263-5312)
- Saeko Yanaka (ORCID: https://orcid.org/0000-0002-3513-5701)
- Haruo Kasahara
Institutions
- National Institutes of Natural Sciences (JP)
- Japan Aerospace Exploration Agency (JP)
- Nagoya City University (JP)
- Spaceflight Industries (United States) (US)
- Institute for Molecular Science (JP)
- National Institute for Physiological Sciences (JP)
- Japan Space Forum (JP)
- Living Systems (United States) (US)
- The Exploratory Research Center on Life and Living Systems (JP)
- Nagoya University (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1021/acschemneuro.5c00217
- Citations
- 3
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 3.49
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Nagoya City University
- Japan Society for the Promotion of Science
- National Institute for Physiological Sciences
- Precursory Research for Embryonic Science and Technology
- Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences