Ca(2+) enhances Aβ polymerization rate and fibrillar stability in a dynamic manner.

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.