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Structure-based inhibitors of amyloid beta core suggest a common interface with tau
Alzheimer’s disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we r...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850776/ https://www.ncbi.nlm.nih.gov/pubmed/31612856 http://dx.doi.org/10.7554/eLife.46924 |
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author | Griner, Sarah L Seidler, Paul Bowler, Jeannette Murray, Kevin A Yang, Tianxiao Peter Sahay, Shruti Sawaya, Michael R Cascio, Duilio Rodriguez, Jose A Philipp, Stephan Sosna, Justyna Glabe, Charles G Gonen, Tamir Eisenberg, David S |
author_facet | Griner, Sarah L Seidler, Paul Bowler, Jeannette Murray, Kevin A Yang, Tianxiao Peter Sahay, Shruti Sawaya, Michael R Cascio, Duilio Rodriguez, Jose A Philipp, Stephan Sosna, Justyna Glabe, Charles G Gonen, Tamir Eisenberg, David S |
author_sort | Griner, Sarah L |
collection | PubMed |
description | Alzheimer’s disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline. |
format | Online Article Text |
id | pubmed-6850776 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-68507762019-11-14 Structure-based inhibitors of amyloid beta core suggest a common interface with tau Griner, Sarah L Seidler, Paul Bowler, Jeannette Murray, Kevin A Yang, Tianxiao Peter Sahay, Shruti Sawaya, Michael R Cascio, Duilio Rodriguez, Jose A Philipp, Stephan Sosna, Justyna Glabe, Charles G Gonen, Tamir Eisenberg, David S eLife Biochemistry and Chemical Biology Alzheimer’s disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline. eLife Sciences Publications, Ltd 2019-10-15 /pmc/articles/PMC6850776/ /pubmed/31612856 http://dx.doi.org/10.7554/eLife.46924 Text en © 2019, Griner et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Griner, Sarah L Seidler, Paul Bowler, Jeannette Murray, Kevin A Yang, Tianxiao Peter Sahay, Shruti Sawaya, Michael R Cascio, Duilio Rodriguez, Jose A Philipp, Stephan Sosna, Justyna Glabe, Charles G Gonen, Tamir Eisenberg, David S Structure-based inhibitors of amyloid beta core suggest a common interface with tau |
title | Structure-based inhibitors of amyloid beta core suggest a common interface with tau |
title_full | Structure-based inhibitors of amyloid beta core suggest a common interface with tau |
title_fullStr | Structure-based inhibitors of amyloid beta core suggest a common interface with tau |
title_full_unstemmed | Structure-based inhibitors of amyloid beta core suggest a common interface with tau |
title_short | Structure-based inhibitors of amyloid beta core suggest a common interface with tau |
title_sort | structure-based inhibitors of amyloid beta core suggest a common interface with tau |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850776/ https://www.ncbi.nlm.nih.gov/pubmed/31612856 http://dx.doi.org/10.7554/eLife.46924 |
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