Cited by 74Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

The N-Terminal Region of Amyloid β Controls the Aggregation Rate and Fibril Stability at Low pH through a Gain of Function Mechanism

Brännström, Kristoffer, Öhman, Anders, Nilsson, Lina, Pihl, Mathias, Sandblad, Linda, Olofsson, Anders·2014·Journal of the American Chemical Society

Abstract

Alzheimer's disease is linked to a pathological polymerization of the endogenous amyloid β-peptide (Aβ) that ultimately forms amyloid plaques within the human brain. We used surface plasmon resonance (SPR) to measure the kinetic properties of Aβ fibril formation under different conditions during the polymerization process. For all polymerization processes, a critical concentration of free monomers, as defined by the dissociation equilibrium constant (K(D)), is required for the buildup of the polymer, for example, amyloid fibrils. At concentrations below the K(D), polymerization cannot occur. However, the K(D) for Aβ has previously been shown to be several orders of magnitude higher than the concentrations found in the cerebrospinal and interstitial fluids of the human brain, and the mechanism by which Aβ amyloid forms in vivo has been a matter of debate. Using SPR, we found that the K(D) of Aβ dramatically decreases as a result of lowering the pH. Importantly, this effect enables Aβ to polymerize within a picomolar concentration range that is close to the physiological Aβ concentration within the human brain. The stabilizing effect is dynamic, fully reversible, and notably pronounced within the pH range found within the endosomal and lysosomal pathways. Through sequential truncation, we show that the N-terminal region of Aβ contributes to the enhanced fibrillar stability due to a gain of function mechanism at low pH. Our results present a possible route for amyloid formation at very low Aβ concentrations and raise the question of whether amyloid formation in vivo is restricted to a low pH environment. These results have general implications for the development of therapeutic interventions.

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Crossref · 10.1021/ja503535m

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Authors
Brännström, K., Öhman, A., Nilsson, L., Pihl, M., Sandblad, L., & Olofsson, A.
Affiliations
Umeå University (SE)
Corresponding author
Olofsson, Anders
Venue
Journal of the American Chemical Society
Published
2014-07-28
Volume
136
Issue
31
Pages
10956-10964
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
OpenAlex
W2041383508
Cited by
74
References
72
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 8 · 2019: 11 · 2018: 14 · 2017: 8 · 2016: 2 · 2015: 2 · 2014: 1
FWCI
2.85
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • V?sterbotten L?ns Landsting
  • Vetenskapsr?det
  • Erling-Persson Family Foundation
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
amyloid-beta, N-terminal domain, amyloid fibril formation, aggregation kinetics, fibril stability, gain-of-function, dissociation equilibrium constant, Alzheimer's disease, amyloid plaques
MeSH terms
Hydrogen-Ion Concentration, Kinetics, Peptide Fragments, Amyloid beta-Peptides, Protein Structure, Secondary, Protein Multimerization, Protein Stability, Protein Aggregates

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