Unraveling the mystery of the unique amyloid plaques in familial Alzheimer's disease

August 30, 2024

This synthetic biology approach opens the door to understanding the structure of β-amyloid and its plaques

An international collaborative research group, including the RIKEN Center for Biosystems Dynamics Research, Tokyo Institute of Technology, and the RIKEN CSRS, has reproduced amyloid fibers that form large aggregates known as ‘cotton-wool’ plaques, which are observed in familial Alzheimer’s disease (AD). Using integrated analysis with cryo-electron microscopy (cryoEM) and solid-state nuclear magnetic resonance (SSNMR), they elucidated novel structural motifs within these cotton-wool plaques.

Familial AD is a subtype of AD associated with genetic mutations and typically occurs at a younger age. Notably, familial AD with a mutation E22G, where glutamic acid at position 22 of β-amyloid (Aβ) is replaced by glycine, shows distinctive pathological features such as cotton-wool plaques.

In this study, the international research group chemically produced Aβ fibers that replicate the characteristics of these cotton-wool plaques without using brain-derived samples. Their analysis using cryoEM and SSNMR revealed a novel structural motif with β-sheets folded in a W-shape. This finding indicates that the uniqueness of the cotton-wool plaques can be explained by the structure of the amyloid fibers rather than brain materials. This research result suggests that differences in fiber structures could significantly impact the pathology and progression of AD. This pioneering research is expected to contribute to drug discovery for early-onset AD and to the understanding of mechanisms underlying the different pathologies in AD subtypes.

Original article

Nature Communications doi: 10.1038/s41467-024-51294-w

M. J. Tehrani, I. Matsuda, A. Yamagata, Y. Kodama, T. Matsunaga, M. Sato, K. Toyooka, D. McElheny, N. Kobayashi, M. Shirouzu, Y. Ishii,

"E22G Aβ40 fibril structure and kinetics illuminate how Aβ40 rather than Aβ42 triggers familial Alzheimer's".

Contact

Kiminori Toyooka; Senior Technical Scientist
Mayuko Sato; Technical Scientist
Mass Spectrometry and Microscopy Unit