Structure based inhibitors of Amyloid Beta core suggest a common interface with Tau
Abstract
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.
Data availability
Diffraction data have been deposited in PDB under the accession code 6O4JSource Data for Toxicity and Seeding data are provided (Figures 2-7)
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Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutationProtein Data Bank, 6O4J.
Article and author information
Author details
Funding
National Institutes of Health (R01 AG029430)
- Sarah L Griner
- Paul Seidler
- Jeannette Bowler
- Kevin A Murray
- Tianxiao Peter Yang
- Shruti Sahay
- Michael R Sawaya
- Duilio Cascio
- Jose A Rodriguez
- David S Eisenberg
Howard Hughes Medical Institute
- Sarah L Griner
- Paul Seidler
- Jeannette Bowler
- Kevin A Murray
- Tianxiao Peter Yang
- Shruti Sahay
- Michael R Sawaya
- Duilio Cascio
- Jose A Rodriguez
- Tamir Gonen
- David S Eisenberg
Cure Alzheimer's Fund
- Stephan Philipp
- Justyna Sosna
- Charles G Glabe
National Institutes of Health (R56 AG061847)
- Paul Seidler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Wesley I Sundquist, University of Utah School of Medicine, United States
Version history
- Received: March 16, 2019
- Accepted: October 4, 2019
- Accepted Manuscript published: October 15, 2019 (version 1)
- Version of Record published: November 12, 2019 (version 2)
Copyright
© 2019, Griner et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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