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Ca2+ enhances Aβ polymerization rate and fibrillar stability in a dynamic manner
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Anders Olofsson)
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
2013 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 450, 189-197 p.Article in journal (Refereed) Published
Abstract [en]

Identifying factors that affect the self-assembly of the amyloid-β peptide (Aβ) is of utmost importance in the quest to understand the molecular mechanisms causing Alzheimer's disease (AD). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and a dysregulated Ca2+ homeostasis frequently correlates with development of AD. The mechanisms regarding Ca2+ binding as well as its effect on fibril kinetics are not fully understood. Using a polymerization assay we show that Ca2+ in a dynamic and reversible manner enhances both the elongation rate and fibrillar stability, where specifically the "dock and lock" phase mechanism is enhanced. Through NMR analysis we found that Ca2+ affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca2+ does not bind the free Aβ monomer. This implies that Ca2+ binding requires an architecture adopted by assembled peptides, and consequently is mediated through intermolecular interactions between adjacent peptides. This gives a mechanistic explanation to the enhancing effect on fibril maturation and indicates structural similarities between prefibrillar structures and mature amyloid. Taken together we expose how Ca2+ levels affect the delicate equilibrium between the monomeric and assembled Aβ and how fluctuations in vivo may contribute to development and progression of the disease.

Place, publisher, year, edition, pages
Portland Press, 2013. Vol. 450, 189-197 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-64160DOI: 10.1042/BJ20121583PubMedID: 23171033OAI: oai:DiVA.org:umu-64160DiVA: diva2:589213
Available from: 2013-01-17 Created: 2013-01-17 Last updated: 2017-12-06Bibliographically approved

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Brännström, KristofferÖhman, AndersLindhagen-Persson, MalinOlofsson, Anders
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CiteExportLink to record
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