Cross-Seeding Controls A beta Fibril Populations and Resulting Functions ...

• Main Authors: Lucas, Michael J., Pan, Henry S., Verbeke, Eric J., Partipilo, Gina M., Helfman, Ethan C., Kann, Leah, Keitz, Benjamin K., Taylor, David W., Webb, Lauren J.
• Format: Text
• Language: English
• Published: The University of Texas at Austin 2021
• Subjects: Fibril; Arctic
• Online Access: https://dx.doi.org/10.26153/tsw/50423; https://repositories.lib.utexas.edu/handle/2152/123629

Amyloid peptides nucleate from monomers to aggregate into fibrils through primary nucleation. Pre-existing fibrils can then act as seeds for additional monomers to fibrillize through secondary nucleation. Both nucleation processes occur simultaneously, yielding a distribution of fibril polymorphs that can generate a spectrum of neurodegenerative effects. Understanding the mechanisms driving polymorph structural distribution during both nucleation processes is important for uncovering fibril structure-function relationships, as well as for creating polymorph distributions in vitro that better match fibril structures found in vivo. Here, we explore how cross-seeding wild-type (WT) Aβ1-40 with Aβ1-40 mutants E22G (Arctic) and E22Δ (Osaka), as well as with WT Aβ1-42, affects the distribution of fibril structural polymorphs and how changes in structural distribution impact toxicity. Transmission electron microscopy analysis revealed that fibril seeds derived from mutants of Aβ1-40 imparted their structure to WT ...