Aβ Oligomer Dissociation Is Catalyzed by Fibril Surfaces
(2024) In ACS Chemical Neuroscience- Abstract
Oligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Their lifetime in solution and abundance, governed by the balance of their sources and sinks, are thus important determinants of disease. While significant advances have been made in elucidating the processes that govern oligomer production, the mechanisms behind their dissociation are still poorly understood. Here, we use chemical kinetic modeling to determine the fate of oligomers formed in vitro and discuss the implications for their abundance in vivo. We discover that oligomeric species formed predominantly on fibril surfaces, a broad class which includes... (More)
Oligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Their lifetime in solution and abundance, governed by the balance of their sources and sinks, are thus important determinants of disease. While significant advances have been made in elucidating the processes that govern oligomer production, the mechanisms behind their dissociation are still poorly understood. Here, we use chemical kinetic modeling to determine the fate of oligomers formed in vitro and discuss the implications for their abundance in vivo. We discover that oligomeric species formed predominantly on fibril surfaces, a broad class which includes the bulk of oligomers formed by the key Alzheimer's disease-associated Aβ peptides, also dissociate overwhelmingly on fibril surfaces, not in solution as had previously been assumed. We monitor this "secondary nucleation in reverse" by measuring the dissociation of Aβ42 oligomers in the presence and absence of fibrils via two distinct experimental methods. Our findings imply that drugs that bind fibril surfaces to inhibit oligomer formation may also inhibit their dissociation, with important implications for rational design of therapeutic strategies for Alzheimer's and other amyloid diseases.
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- author
- Dear, Alexander J. LU ; Thacker, Dev LU ; Wennmalm, Stefan ; Ortigosa-Pascual, Lei LU ; Andrzejewska, Ewa A. LU ; Meisl, Georg ; Linse, Sara LU and Knowles, Tuomas P. J.
- organization
- publishing date
- 2024-05-24
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- ACS Chemical Neuroscience
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:85194238974
- pmid:38785363
- ISSN
- 1948-7193
- DOI
- 10.1021/acschemneuro.4c00127
- language
- English
- LU publication?
- yes
- id
- a6b37814-8676-422d-910e-856c70bc6c55
- date added to LUP
- 2024-05-25 21:37:29
- date last changed
- 2024-06-21 04:48:01
@article{a6b37814-8676-422d-910e-856c70bc6c55,
abstract = {{<p>Oligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Their lifetime in solution and abundance, governed by the balance of their sources and sinks, are thus important determinants of disease. While significant advances have been made in elucidating the processes that govern oligomer production, the mechanisms behind their dissociation are still poorly understood. Here, we use chemical kinetic modeling to determine the fate of oligomers formed in vitro and discuss the implications for their abundance in vivo. We discover that oligomeric species formed predominantly on fibril surfaces, a broad class which includes the bulk of oligomers formed by the key Alzheimer's disease-associated Aβ peptides, also dissociate overwhelmingly on fibril surfaces, not in solution as had previously been assumed. We monitor this "secondary nucleation in reverse" by measuring the dissociation of Aβ42 oligomers in the presence and absence of fibrils via two distinct experimental methods. Our findings imply that drugs that bind fibril surfaces to inhibit oligomer formation may also inhibit their dissociation, with important implications for rational design of therapeutic strategies for Alzheimer's and other amyloid diseases.</p>}},
author = {{Dear, Alexander J. and Thacker, Dev and Wennmalm, Stefan and Ortigosa-Pascual, Lei and Andrzejewska, Ewa A. and Meisl, Georg and Linse, Sara and Knowles, Tuomas P. J.}},
issn = {{1948-7193}},
language = {{eng}},
month = {{05}},
publisher = {{The American Chemical Society (ACS)}},
series = {{ACS Chemical Neuroscience}},
title = {{Aβ Oligomer Dissociation Is Catalyzed by Fibril Surfaces}},
url = {{http://dx.doi.org/10.1021/acschemneuro.4c00127}},
doi = {{10.1021/acschemneuro.4c00127}},
year = {{2024}},
}