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Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR
[Image: see text] 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-specifi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2015
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462565/ https://www.ncbi.nlm.nih.gov/pubmed/25938164 http://dx.doi.org/10.1021/jacs.5b03373 |
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author | Parthasarathy, Sudhakar Inoue, Masafumi Xiao, Yiling Matsumura, Yoshitaka Nabeshima, Yo-ichi Hoshi, Minako Ishii, Yoshitaka |
author_facet | Parthasarathy, Sudhakar Inoue, Masafumi Xiao, Yiling Matsumura, Yoshitaka Nabeshima, Yo-ichi Hoshi, Minako Ishii, Yoshitaka |
author_sort | Parthasarathy, Sudhakar |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-4462565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-44625652016-05-04 Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR Parthasarathy, Sudhakar Inoue, Masafumi Xiao, Yiling Matsumura, Yoshitaka Nabeshima, Yo-ichi Hoshi, Minako Ishii, Yoshitaka J Am Chem Soc [Image: see text] 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. American Chemical Society 2015-05-04 2015-05-27 /pmc/articles/PMC4462565/ /pubmed/25938164 http://dx.doi.org/10.1021/jacs.5b03373 Text en Copyright © 2015 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
spellingShingle | Parthasarathy, Sudhakar Inoue, Masafumi Xiao, Yiling Matsumura, Yoshitaka Nabeshima, Yo-ichi Hoshi, Minako Ishii, Yoshitaka Structural Insight into an Alzheimer’s Brain-Derived Spherical Assembly of Amyloid β by Solid-State NMR |
title | Structural
Insight into an Alzheimer’s Brain-Derived
Spherical Assembly of Amyloid β by Solid-State NMR |
title_full | Structural
Insight into an Alzheimer’s Brain-Derived
Spherical Assembly of Amyloid β by Solid-State NMR |
title_fullStr | Structural
Insight into an Alzheimer’s Brain-Derived
Spherical Assembly of Amyloid β by Solid-State NMR |
title_full_unstemmed | Structural
Insight into an Alzheimer’s Brain-Derived
Spherical Assembly of Amyloid β by Solid-State NMR |
title_short | Structural
Insight into an Alzheimer’s Brain-Derived
Spherical Assembly of Amyloid β by Solid-State NMR |
title_sort | structural
insight into an alzheimer’s brain-derived
spherical assembly of amyloid β by solid-state nmr |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462565/ https://www.ncbi.nlm.nih.gov/pubmed/25938164 http://dx.doi.org/10.1021/jacs.5b03373 |
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