General integrated rate law for complex self-assembly reactions reveals the mechanism of amyloid-beta coaggregation
(2025) In Physical Chemistry Chemical Physics- Abstract
Analyzing kinetic experiments on protein aggregation using integrated rate laws has led to numerous advances in our understanding of the fundamental chemical mechanisms behind amyloidogenic disorders such as Alzheimer's and Parkinson's diseases. However, the description of biologically relevant processes may require rate equations that are too complex to solve using existing methods, hindering mechanistic insights into these processes. An example of significance is coaggregation in environments containing multiple amyloid-beta (Aβ) peptide alloforms, which may play a crucial role in the biochemistry of Alzheimer's disease but whose mechanism is still poorly understood. Here, we use the mathematics of Lie symmetry to derive a general... (More)
Analyzing kinetic experiments on protein aggregation using integrated rate laws has led to numerous advances in our understanding of the fundamental chemical mechanisms behind amyloidogenic disorders such as Alzheimer's and Parkinson's diseases. However, the description of biologically relevant processes may require rate equations that are too complex to solve using existing methods, hindering mechanistic insights into these processes. An example of significance is coaggregation in environments containing multiple amyloid-beta (Aβ) peptide alloforms, which may play a crucial role in the biochemistry of Alzheimer's disease but whose mechanism is still poorly understood. Here, we use the mathematics of Lie symmetry to derive a general integrated rate law valid for most plausible linear self-assembly reactions. We use it in conjunction with experimental data to determine the mechanism of coaggregation of the most physiologically abundant Aβ alloforms: Aβ42, Aβ40, Aβ38 and Aβ37 peptides. We find that Aβ42 fibril surfaces catalyze the formation of co-oligomers, which accelerate new Aβ40, Aβ38 and Aβ37 fibril formation whilst inhibiting secondary nucleation of new Aβ42 fibrils. The simplicity, accuracy and broad applicability of our general integrated rate law will enable kinetic analysis of more complex filamentous self-assembly reactions, both with and without coaggregation.
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- author
- Dear, Alexander J. LU ; Meisl, Georg ; Axell, Emil LU ; Yang, Xiaoting LU ; Cukalevski, Risto LU ; Michaels, Thomas C.T. ; Linse, Sara LU and Mahadevan, L.
- organization
- publishing date
- 2025
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- Physical Chemistry Chemical Physics
- publisher
- Royal Society of Chemistry
- external identifiers
-
- scopus:105018727508
- pmid:41004126
- ISSN
- 1463-9076
- DOI
- 10.1039/d5cp01288k
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2025 The Royal Society of Chemistry.
- id
- cb5a023c-1fed-4375-82d0-19bd90c20534
- date added to LUP
- 2026-01-22 14:51:44
- date last changed
- 2026-01-22 14:52:39
@article{cb5a023c-1fed-4375-82d0-19bd90c20534,
abstract = {{<p>Analyzing kinetic experiments on protein aggregation using integrated rate laws has led to numerous advances in our understanding of the fundamental chemical mechanisms behind amyloidogenic disorders such as Alzheimer's and Parkinson's diseases. However, the description of biologically relevant processes may require rate equations that are too complex to solve using existing methods, hindering mechanistic insights into these processes. An example of significance is coaggregation in environments containing multiple amyloid-beta (Aβ) peptide alloforms, which may play a crucial role in the biochemistry of Alzheimer's disease but whose mechanism is still poorly understood. Here, we use the mathematics of Lie symmetry to derive a general integrated rate law valid for most plausible linear self-assembly reactions. We use it in conjunction with experimental data to determine the mechanism of coaggregation of the most physiologically abundant Aβ alloforms: Aβ42, Aβ40, Aβ38 and Aβ37 peptides. We find that Aβ42 fibril surfaces catalyze the formation of co-oligomers, which accelerate new Aβ40, Aβ38 and Aβ37 fibril formation whilst inhibiting secondary nucleation of new Aβ42 fibrils. The simplicity, accuracy and broad applicability of our general integrated rate law will enable kinetic analysis of more complex filamentous self-assembly reactions, both with and without coaggregation.</p>}},
author = {{Dear, Alexander J. and Meisl, Georg and Axell, Emil and Yang, Xiaoting and Cukalevski, Risto and Michaels, Thomas C.T. and Linse, Sara and Mahadevan, L.}},
issn = {{1463-9076}},
language = {{eng}},
publisher = {{Royal Society of Chemistry}},
series = {{Physical Chemistry Chemical Physics}},
title = {{General integrated rate law for complex self-assembly reactions reveals the mechanism of amyloid-beta coaggregation}},
url = {{http://dx.doi.org/10.1039/d5cp01288k}},
doi = {{10.1039/d5cp01288k}},
year = {{2025}},
}