Exploring the thermodynamic and kinetic landscape of amyloid fibril formation

The purpose of the work that forms the basis of this thesis has been to investigate fundamental properties of amyloid β and tau self-assembly and their solubility. The results of this research are presented as five research articles. In Paper I, a solubility assay for determining the solubility of amyloid proteins is developed and its use demonstrated for the Aβ40 peptide. Paper II finds that tau truncated of its flexible regions adjacent to the amyloid core, (tau 304-380C322S) spontaneously forms fibrils without the use of external inducers and that the proliferation of fibrils occurs through secondary
nucleation. Next, in Paper III, the methodology developed in Paper I is applied to the fragment of tau from Paper II, and its solubility is established. Paper IV explores how fluid shear forces influences the microscopic steps of fibril formation and find that primary and secondary nucleation is increased by mild shear, while elongation and fragmentation is unaffected for Aβ42. The increase in secondary nucleation, in turn increases the oligomer population. Paper V explores one of the body’s own defense mechanisms against protein misfolding, the molecular chaperone DNAJB6b, and how its assembly state affects the potency of Aβ42 aggregation inhibition.

Collectivly, this work provides new insights and avenues for continued research that hopefully one day may help improve the prospects and quality of life for the individuals suffering from AD.