Amyloid Fibril Structures

Amyloids are highly ordered protein aggregates implicated in various neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s (AD) diseases, as well as metabolic disorders like Type 2 Diabetes. These fibrillar protein assemblies are central to disease pathology, forming extracellular plaques or intracellular inclusions that disrupt cellular function. Despite their importance, studying amyloid fibril structures has been historically challenging due to their insolubility and polymorphic nature.

However, the advent of cryo-electron microscopy (cryo-EM) has revolutionized the field by enabling high-resolution structural determination of amyloid fibrils. In 2017, the Schröder group made a pioneering contribution by being the first to solve the high-resolution structure of an amyloid-beta (Aβ) fibril associated with AD.

By characterizing Aβ fibrils from multiple transgenic mouse models, we further identified both novel and human-relevant fibril polymorphs, emphasizing the importance of selecting appropriate models for preclinical drug development. In the context of Type 2 Diabetes, we solved the structures of fibril polymorphs of islet amyloid polypeptide (IAPP), uncovering structural similarities with Alzheimer’s Aβ fibrils and suggesting potential cross-seeding mechanisms between these diseases, which provides a potential explanation for the known epidemiological link between AD and Diabetes.

Lipids play a crucial in both in AD and in PD. For Parkinson’s disease, we discovered lipid-bound α-synuclein fibrils with distinct protofilament arrangements, which reveals how these fibrils disrupt cellular vesicles and contribute to neuronal toxicity. Furthermore, we demonstrated that Aβ fibrils extract lipids from vesicles and form stable fibril-lipid complexes, which provides a mechanistic understanding of the involvement of lipids in amyloid plaque formation in AD.

These findings emphasize the diverse structures and mechanisms of amyloid fibrils, which provide valuable insights for developing therapeutic strategies to address amyloid-related diseases.