Early stages and final results of amyloid-beta self-assembly

Amyloid-β (Aβ) peptides self-assemble into a wide variety of states, ranging from partially structured oligomers comprising 2-12 molecules to polymorphic, highly structured, micron-long fibrils comprising roughly 5000 molecules. I will present results from several recent studies in which we have characterized structural features of oligomers in the earliest stages of Aβ self-assembly, using novel time-resolved solid state NMR and time-resolved light scattering measurements, and the full structures of 40- and 42-residue Aβ fibrils that develop in human brain tissue, using solid state NMR and cryoEM methods. In the time-resolved studies, we find that Aβ peptides develop β-strand secondary structure within 1 ms of the initiation of self-assembly by a rapid change in pH, when the average assembly is only a dimer. Remarkably, the solid state NMR spectra of freeze-trapped samples show very little change as the average oligomer size increases from 2 to >20 molecules over a 30 s period. In the structural studies of brain-derived fibrils, we find that the predominant brain-derived 40-residue Aβ40 fibril polymorph is nearly identical to one of the polymorphs that can be grown in vitro under quiescent conditions. In contrast, structures of two predominant 42-residue Aβ42 fibril polymorphs derived from brain tissue differ significantly from structures of in vitro polymorphs that have been solved previously by other labs.