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- Title
Ca<sup>2+</sup> enhances Aβ polymerization rate and fibrillar stability in a dynamic manner.
- Authors
BRÄNNSTRÖM, Kristoffer; ÖHMAN, Anders; LINDHAGEN-PERSSON, Malin; OLOFSSON, Anders
- Abstract
Identifying factors that affect the self-assembly of Aβ (amyloid- β peptide) is of utmost importance in the quest to understand the molecular mechanisms causing AD (Alzheimer's disease). Ca2+ has previously been shown to accelerate both Aβ fibril nucleation and maturation, and dysregulated Ca2+ homoeostasis 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 show 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.
- Publication
Biochemical Journal, 2013, Vol 450, Issue 1, p189
- ISSN
0264-6021
- Publication type
Academic Journal
- DOI
10.1042/BJ20121583