title: Ca(2+) enhances Aβ polymerization rate and fibrillar stability in a dynamic manner.
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). Ca(2+) has previously been shown to accelerate both Aβ fibril nucleation and maturation, and dysregulated Ca(2+) homoeostasis frequently correlates with development of AD. The mechanisms regarding Ca(2+) binding, as well as its effect on fibril kinetics, are not fully understood. Using a polymerization assay we show that Ca(2+) 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 Ca(2+) affects the fibrillar architecture. In addition, and unexpectedly, we found that Ca(2+) does not bind the free Aβ monomer. This implies that Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Brännström
authors.forename: Anders
authors.initials: A
authors.lastname: Ohman
authors.forename: Malin
authors.initials: M
authors.lastname: Lindhagen-Persson
authors.forename: Anders
authors.initials: A
authors.lastname: Olofsson
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D058105:Polymerization; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D002118:Calcium