Structure based inhibitors of Amyloid Beta core suggest a common interface with Tau

Abstract
Data availability
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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)

The following data sets were generated

1. Griner SL
2. Sawaya MR
3. Rodriguez JA
4. Cascio D
5. Gonen T
(2019) Amyloid Beta KLVFFAENVGS 16-26 D23N Iowa mutation
Protein Data Bank, 6O4J.

https://www.rcsb.org/structure/6O4J

Article and author information

Author details

Sarah L Griner

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

For correspondence
sgriner@ucla.edu

Competing interests
No competing interests declared.
Paul Seidler

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Jeannette Bowler

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Kevin A Murray

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Tianxiao Peter Yang

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4479-5154
Shruti Sahay

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Michael R Sawaya

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Duilio Cascio

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Jose A Rodriguez

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

Competing interests
No competing interests declared.
Stephan Philipp

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States

Competing interests
No competing interests declared.
Justyna Sosna

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States

Competing interests
No competing interests declared.
Charles G Glabe

Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States

Competing interests
No competing interests declared.
Tamir Gonen

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-9254-4069
David S Eisenberg

Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States

For correspondence
david@mbi.ucla.edu

Competing interests
David S Eisenberg, is a SAB member and equity holder in ADRx, Inc.

"This ORCID iD identifies the author of this article:" 0000-0003-2432-5419

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.

Copyright

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.