The Properties of Amyloid-beta Fibrils Are Determined by their Path of Formation

Fibril formation of the amyloid-6 peptide (A(3) follows a nucleation-dependent polymerization process and is associated with Alzheimer's disease. Several different lengths of A beta are observed in vivo, but A beta 1-40 and A beta 1-42 are the dominant forms. The fibril architectures of A beta 1-40 and A beta 1-42 differ and A beta 1-42 assemblies are generally considered more pathogenic. We show here that monomeric A beta 1-42 can be cross-templated and incorporated into the ends of A beta 1-40 fibrils, while incorporation of A beta 1-40 monomers into A beta 1-42 fibrils is very poor. We also show that via cross-templating incorporated A beta monomers acquire the properties of the parental ;fibrils. The suppressed ability of A beta 1-40 to incorporate into the ends of A beta 1-42 fibrils and the capacity of A beta 1-42 monomers to adopt the properties of A beta 1-40 fibrils may thus represent two mechanisms reducing the total load of fibrils having the intrinsic, and possibly pathogenic, features of A beta 1-42 fibrils in vivo. We also show that the transfer of fibrillar properties is restricted to fibril-end templating and does not apply to cross-nucleation via the recently described path of surface-catalyzed secondary nucleation, which instead generates similar structures to those acquired via de novo primary nucleation in the absence of catalyzing seeds. Taken together these results uncover an intrinsic barrier that prevents A beta 1-40 from adopting the fibrillar properties of A beta 1-42 and exposes that the transfer of properties between amyloid-6 fibrils are determined by their path of formation. (C) 2018 Published by Elsevier Ltd.