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Cited by 121Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Structure-based inhibitors of amyloid beta core suggest a common interface with tau

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Griner, Sarah L, Seidler, Paul, Bowler, Jeannette, Murray, Kevin A, Yang, Tianxiao Peter, Sahay, Shruti, Sawaya, Michael R, Cascio, Duilio +6 more·2019·eLife
DOI 10.7554/elife.46924PMC PMC6850776
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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.

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  • Short peptides with altered amino acid sequences that target cross-sectional interfaces have been successfully employed in capping of various amyloid fibrils and inhibition of seeding.

    “Notably, short peptides with altered amino acid sequences that target the cross-sectional interfaces of aggregation-prone regions have been successfully employed in the capping of various amyloid fibrils and the inhibition of seeding (63, 64, 65, 66).”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [65]

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Authors
Griner, S. L., Seidler, P., Bowler, J., Murray, K. A., Yang, T. P., Sahay, S., Sawaya, M. R., Cascio, D., Rodriguez, J. A., Philipp, S., Sosna, J., Glabe, C. G., Gonen, T., & Eisenberg, D. S.
Affiliations
  • Howard Hughes Medical Institute (US)
  • UCLA-DOE Institute, Department of Biological Chemistry, Molecular Biology Institute, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
  • University of California, Irvine (US)
  • King Abdulaziz University (SA)
Corresponding author
  • Griner, Sarah L
  • Eisenberg, David S
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2019-10-15
Volume
8
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.46924
PMC
PMC6850776
OpenAlex
W2981228863
Cited by
121
References
8
Citations by year
2026: 11 · 2025: 14 · 2024: 14 · 2023: 16 · 2022: 30 · 2021: 20 · 2020: 15 · 2018: 1
FWCI
11.15
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (R01 AG029430, R56 AG061847, R01 AG054022)
  • Howard Hughes Medical Institute
  • Cure Alzheimer's Fund
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta, tau protein, Alzheimer's disease, peptide inhibitors, amyloid-beta aggregation, tau aggregation, cross-seeding, oligomeric amyloid, self-seeding, neurofibrillary tangles
MeSH terms
Animals, Humans, Protein Binding, Protein Conformation, Molecular Structure, Amyloid beta-Peptides, tau Proteins, Crystallography, X-Ray

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