Structural Insight into an Alzheimer's Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR.
Accumulating evidence suggests that various neurodegenerative diseases, including Alzheimer's disease (AD), are linked to cytotoxic diffusible aggregates of amyloid proteins, which are metastable intermediate species in protein misfolding. This study presents the first site-specific structural study on an intermediate called amylospheroid (ASPD), an AD-derived neurotoxin composed of oligomeric amyloid-β (Aβ). Electron microscopy and immunological analyses using ASPD-specific "conformational" antibodies established synthetic ASPD for the 42-residue Aβ(1-42) as an excellent structural/morphological analogue of native ASPD extracted from AD patients, the level of which correlates with the severity of AD. (13)C solid-state NMR analyses of approximately 20 residues and interstrand distances demonstrated that the synthetic ASPD is made of a homogeneous single conformer containing parallel β-sheets. These results provide profound insight into the native ASPD, indicating that Aβ is likely to self-assemble into the toxic intermediate with β-sheet structures in AD brains. This approach can be applied to various intermediates relevant to amyloid diseases.
†Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
Sudhakar
S
Parthasarathy
‡TAO Health Life Pharma Co. Ltd., Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan.|§Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan.
Masafumi
M
Inoue
†Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
Yiling
Y
Xiao
‡TAO Health Life Pharma Co. Ltd., Medical Innovation Center in Kyoto University, Kyoto 606-8507, Japan.|§Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan.
Yoshitaka
Y
Matsumura
§Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan.
Yo-ichi
Y
Nabeshima
§Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan.|∥Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Minako
M
Hoshi
†Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States.|⊥UIC Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois 60607, United States.
Yoshitaka
Y
Ishii
D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D006801:Humans; D008854:Microscopy, Electron; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular
D000682:Amyloid