Cross-seeding of WT amyloid-β with Arctic but not Italian familial mutants accelerates fibril formation in Alzheimer's disease

Alzheimer's disease (AD) involves the neurotoxic self-assembly of a 40 and 42 residue peptide, Amyloid-beta (A beta). Inherited early-onset AD can be caused by single point mutations within the A beta sequence, including Arctic (E22G) and Italian (E22K) familial mutants. These mutations are heterozygous, resulting in an equal proportion of the WT and mutant A beta isoform expression. It is therefore important to understand how these mixtures of A beta isoforms interact with each other and influence the kinetics and morphology of their assembly into oligomers and fibrils. Using small amounts of nucleating fibril seeds, here, we systematically monitored the kinetics of fibril formation, comparing self-seeding with cross-seeding behavior of a range of isoform mixtures of A beta 42 and A beta 40. We confirm that A beta 40(WT) does not readily cross-seed A beta 42(WT) fibril formation. In contrast, fibril formation of A beta 40(Arctic) is hugely accelerated by A beta 42(WT) fibrils, causing an eight-fold reduction in the lag-time to fibrillization. We propose that cross-seeding between the more abundant A beta 40(Arctic) and A beta 42(WT) may be important for driving early-onset AD and will propagate fibril morphology as indicated by fibril twist periodicity. This kinetic behavior is not emulated by the Italian mutant, where minimal cross-seeding is observed. In addition, we studied the cross-seeding behavior of a C-terminal-amidated A beta 42 analog to probe the coulombic charge interplay between Glu22/Asp23/Lys28 and the C-terminal carboxylate. Overall, these studies highlight the role of cross-seeding between WT and mutant A beta 40/42 isoforms, which can impact the rate and structure of fibril assembly.

Automated summary

Alzheimer's disease involves the neurotoxic self-assembly of Amyloid-beta peptides, and different mutant forms have varying effects on the kinetics and morphology of their assembly. Studies suggest that Aβ42(WT) accelerates fibril formation of Aβ40(Arctic), which may be relevant to the development of early-onset AD.