Understanding and Controlling Amyloid Polymorphism: From Test Tube to Tissue (360G-Wellcome-327928_Z_25_Z)

Amyloid disease have been called ‘the next pandemic’, with Alzheimer’s and Parkinson’s alone predicted to affect >66m people worldwide, costing >$4t p.a. (by 2030). Despite recent breakthroughs, how and why amyloid formation causes disease remains unclear, and therapies are few or ineffectual. However, exciting tools to visualise amyloid structures in vitro and in situ, and to track them with time, have revealed three remarkable findings: that (i) amyloid fibrils formed in vitro are polymorphic, while those extracted from patient samples are much more homogeneous and even disease-specific; (ii) amyloid fibril structures change with time, even though fibril yield is at steady state and (iii) that small molecules can ‘steer’ aggregation to new fibril products. Spearheaded by these findings, and combining kinetic assays, structural analysis, and experiments in cells and in tissue, we propose a 6-year programme that will: (i) provide a new molecular understanding of how amyloid folds are assembled; (ii) develop new molecules and strategies to kinetically-control amyloid polymorphism; and (iii) determine whether and how amyloid structure and polymorphism changes in a pathological setting. The outcome will be a breakthrough in understanding of amyloid polymorphism and how polymorphism contributes to cellular dysfunction and disease.