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The temperature dependence of amyloid β solubility reveals the hydrophobic effect as the main driving force for fibril formation

Lindberg, Max LU orcid ; Hu, Jing LU ; Thacker, Dev LU ; Sparr, Emma LU and Linse, Sara LU (2026) In Proceedings of the National Academy of Sciences of the United States of America 123(17).
Abstract

The aggregation of amyloid proteins into fibrillar and oligomeric aggregates is linked to a number of neurodegenerative diseases. While the disease onset remains elusive in many cases, an understanding of the driving forces for the aggregation may help finding possible causes. While effects on amyloid formation kinetics are more commonly studied, gaining insights into these driving forces require a thermodynamic approach with equilibrium measurements. Here we investigate the temperature dependence of the solubility of the amyloid beta peptide, Aβ42, related to Alzheimer’s disease, using high-performance liquid chromatography coupled to a mass spectrometer and circular dichroism spectroscopy. Samples of 8 to 50 μM Aβ42 were incubated for... (More)

The aggregation of amyloid proteins into fibrillar and oligomeric aggregates is linked to a number of neurodegenerative diseases. While the disease onset remains elusive in many cases, an understanding of the driving forces for the aggregation may help finding possible causes. While effects on amyloid formation kinetics are more commonly studied, gaining insights into these driving forces require a thermodynamic approach with equilibrium measurements. Here we investigate the temperature dependence of the solubility of the amyloid beta peptide, Aβ42, related to Alzheimer’s disease, using high-performance liquid chromatography coupled to a mass spectrometer and circular dichroism spectroscopy. Samples of 8 to 50 μM Aβ42 were incubated for up to 168 h at pH 8.0 and moderate ionic strength at multiple temperatures in the range of 5 to 80 ◦C. The remaining monomer concentration was measured after 48 to 168 h, with little change in between suggesting that equilibrium is approached at 168 h. The lowest solubility of 20 ± 10 nM is found around body temperature, with higher solubility at both lower and higher temperatures. This nonmonotonic temperature dependence is indicative of the hydrophobic effect being a major driving force for the fibril formation of this peptide.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aβ | Alzheimer’s disease | thermodynamics | self-assembly | β-amyloid
in
Proceedings of the National Academy of Sciences of the United States of America
volume
123
issue
17
article number
e2531916123
publisher
National Academy of Sciences
external identifiers
  • pmid:42008670
  • scopus:105036254408
ISSN
0027-8424
DOI
10.1073/pnas.2531916123
language
English
LU publication?
yes
additional info
Publisher Copyright: Copyright © 2026 the Author(s).
id
2cef1c23-d337-40aa-ae02-fc10467e3e18
date added to LUP
2026-06-29 09:50:21
date last changed
2026-06-30 03:18:40
@article{2cef1c23-d337-40aa-ae02-fc10467e3e18,
  abstract     = {{<p>The aggregation of amyloid proteins into fibrillar and oligomeric aggregates is linked to a number of neurodegenerative diseases. While the disease onset remains elusive in many cases, an understanding of the driving forces for the aggregation may help finding possible causes. While effects on amyloid formation kinetics are more commonly studied, gaining insights into these driving forces require a thermodynamic approach with equilibrium measurements. Here we investigate the temperature dependence of the solubility of the amyloid beta peptide, Aβ42, related to Alzheimer’s disease, using high-performance liquid chromatography coupled to a mass spectrometer and circular dichroism spectroscopy. Samples of 8 to 50 μM Aβ42 were incubated for up to 168 h at pH 8.0 and moderate ionic strength at multiple temperatures in the range of 5 to 80 <sup>◦</sup>C. The remaining monomer concentration was measured after 48 to 168 h, with little change in between suggesting that equilibrium is approached at 168 h. The lowest solubility of 20 ± 10 nM is found around body temperature, with higher solubility at both lower and higher temperatures. This nonmonotonic temperature dependence is indicative of the hydrophobic effect being a major driving force for the fibril formation of this peptide.</p>}},
  author       = {{Lindberg, Max and Hu, Jing and Thacker, Dev and Sparr, Emma and Linse, Sara}},
  issn         = {{0027-8424}},
  keywords     = {{Aβ | Alzheimer’s disease | thermodynamics | self-assembly | β-amyloid}},
  language     = {{eng}},
  number       = {{17}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{The temperature dependence of amyloid β solubility reveals the hydrophobic effect as the main driving force for fibril formation}},
  url          = {{http://dx.doi.org/10.1073/pnas.2531916123}},
  doi          = {{10.1073/pnas.2531916123}},
  volume       = {{123}},
  year         = {{2026}},
}