N-Terminal Extensions Retard Aβ42 Fibril Formation but Allow Cross-Seeding and Coaggregation with Aβ42

• DOI: 10.1021/jacs.5b07849
• Publication Date: 2015-11-04T19:43:28Z
• Authors: Olga Szczepankiewicz; Björn Linse; Georg Meisl; Eva Thulin; Birgitta Frohm; Carlo Sala Frigerio; Michael T. Colvin; Angela C. Jacavone; Robert G. Griffin; Tuomas Knowles; Dominic M. Walsh; Sara Linse
• Keywords: Thioflavin; Amyloid (mycology); Cleavage (geology); Amyloid disease

Amyloid β-protein (Aβ) sequence length variants with varying aggregation propensity coexist in vivo, where coaggregation and cross-catalysis phenomena may affect the process. Until recently, naturally occurring amyloid were believed to begin at or after canonical β-secretase cleavage site within precursor. However, N-terminally extended forms of Aβ (NTE-Aβ) recently discovered contribute Alzheimer's disease. Here, we have used thioflavin T fluorescence study kinetics Aβ42 N-terminal extensions 5-40 residues, transmission electron microscopy analyze end states. We find that all form fibrils similar morphology as Aβ42, but half-time (t1/2) increases exponentially extension length. Monte Carlo simulations model peptides suggest retardation is due an underlying general physicochemical effect involving reduced frequency productive molecular encounters. Indeed, global kinetic analyses reveal NTE-Aβ42s via same mechanism microscopic rate constants (primary secondary nucleation, elongation) are for variants. Still, NTE-Aβ42 coaggregate mixed either catalyze monomers. monomers display kinds seeds implying termini interfere ability nucleate elongate. Cross-seeding therefore represent important contribution vivo formation assemblies be