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The N-terminal Region of Amyloid β Controls the Aggregation Rate and Fibril Stability at Low pH Through a Gain of Function Mechanism
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
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2014 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 136, no 31, 10956-10964 p.Article in journal (Refereed) Published
Abstract [en]

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 (KD), is required for the buildup of the polymer, for example, amyloid fibrils. At concentrations below the KD, polymerization cannot occur. However, the KD 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 KD 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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2014. Vol. 136, no 31, 10956-10964 p.
Keyword [en]
Mediator, Med25, Dreb2a, VP16, conformational changes, NMR, ITC
National Category
URN: urn:nbn:se:umu:diva-91524DOI: 10.1021/ja503535mISI: 000340079800030PubMedID: 25014209OAI: diva2:736884
Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2015-12-21Bibliographically approved

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Brännström, KristofferÖhman, AndersNilsson, LinaPihl, MathiasSandblad, LindaOlofsson, Anders
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Department of Medical Biochemistry and BiophysicsClinical NeuroscienceDepartment of ChemistryDepartment of Molecular Biology (Faculty of Medicine)
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