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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
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.
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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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