Probing differences among Aβ oligomers with two triangular trimers derived from Aβ

Adam G. Kreutzer, Gretchen Guaglianone, Stan Yoo, Chelsea Marie T. Parrocha, Sarah M. Ruttenberg, Ryan J. Malonis, Karen Tong, Yu Fu Lin, Jennifer T. Nguyen, William J. Howitz, Michelle N. Diab, Imane L. Hamza, Jonathan R. Lai, Vicki H. Wysocki, James S. Nowick

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The assembly of the β-amyloid peptide (Aβ) to form oligomers and fibrils is closely associated with the pathogenesis and progression of Alzheimer’s disease. Aβ is a shape-shifting peptide capable of adopting many conformations and folds within the multitude of oligomers and fibrils the peptide forms. These properties have precluded detailed structural elucidation and biological characterization of homogeneous, well-defined Aβ oligomers. In this paper, we compare the structural, biophysical, and biological characteristics of two different covalently stabilized isomorphic trimers derived from the central and C-terminal regions Aβ. X-ray crystallography reveals the structures of the trimers and shows that each trimer forms a ball-shaped dodecamer. Solution-phase and cell-based studies demonstrate that the two trimers exhibit markedly different assembly and biological properties. One trimer forms small soluble oligomers that enter cells through endocytosis and activate capase-3/7-mediated apoptosis, while the other trimer forms large insoluble aggregates that accumulate on the outer plasma membrane and elicit cellular toxicity through an apoptosis-independent mechanism. The two trimers also exhibit different effects on the aggregation, toxicity, and cellular interaction of full-length Aβ, with one trimer showing a greater propensity to interact with Aβ than the other. The studies described in this paper indicate that the two trimers share structural, biophysical, and biological characteristics with oligomers of full-length Aβ. The varying structural, assembly, and biological characteristics of the two trimers provide a working model for how different Aβ trimers can assemble and lead to different biological effects, which may help shed light on the differences among Aβ oligomers.

Original languageEnglish (US)
Article numbere2219216120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number22
DOIs
StatePublished - May 30 2023
Externally publishedYes

Bibliographical note

Funding Information:
We thank Benjamin Katz and Dr. Felix Grun at the University of California Irvine Mass Spectrometry Facility for assistance with liquid chromatography-mass spectrometry (LC-MS), Dr. Huiying Li for assistance with operating the X-ray diffractometer, and Dr. Dmitry Fishman at the University of California Irvine Laser Spectroscopy Labs for assistance with circular dichroism (CD) spectroscopy. We also thank the NIH National Institute on Aging (NIA) for funding (Grants AG062296 and AG072587).

Funding Information:
ACKNOWLEDGMENTS. We thank Benjamin Katz and Dr. Felix Grun at the University of California Irvine Mass Spectrometry Facility for assistance with liquid chromatography-mass spectrometry (LC-MS), Dr. Huiying Li for assistance with operating the X-ray diffractometer, and Dr. Dmitry Fishman at the University of California Irvine Laser Spectroscopy Labs for assistance with circular dichroism (CD) spectroscopy. We also thank the NIH National Institute on Aging (NIA) for funding (Grants AG062296 and AG072587).

Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.

Keywords

  • Alzheimer’s disease
  • Aβ oligomers
  • cellular toxicity
  • native mass spectrometry
  • X-ray crystallography

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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