Chapter 5: Structural Insights on Aggregation Species of Aβ and Tau, and Their Implications in Alzheimer's Disease Check Access

Amyloid aggregation of Aβ and Tau are closely associated with Alzheimer's disease (AD). Structural investigation of the aggregated species of Aβ and Tau including the oligomeric and fibrillar species is of importance to understand the molecular grammar of their assembly and pathological roles in the progression of AD. The inherently unstable and heterogeneous nature of amyloid oligomers exclude their structural characterization at the atomic level. In contrast, the atomic structures of several Aβ and Tau fibrils prepared in vitro or directly extracted from the brain tissues of AD patients have been determined by cryogenic electron microscopy (cryo-EM) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy recently. Both Aβ and Tau can form multiple fibril strains with a high structural diversity, so called fibril polymorphs. Post-translational modification (PTM) and metabolic co-factors may play an important role in determining the fibril polymorph. Importantly, different polymorphic fibril structures lead to distinct physiopathology in cells and animal models, which may explain the high clinical heterogeneity of AD and other neurodegenerative diseases. How different fibril polymorphs determine their pathology in disease is an outstanding question to be answered in the future.