Solid State NMR Structural Studies of 42-Residue β-Amyloid Aggregates in Alzheimer’s Disease

This dissertation research focuses on studying the structures and propagation-properties of misfolded aggregates of Aβ(1–42) using solid-state NMR (SSNMR) and other methods. Increasing evidences suggest that the formation and propagation of amyloid aggregates of Aβ(1–42), rather than the more abundant Aβ(1–40), provoke the Alzheimer’s cascade. Despite its denoting pathological-relevance in Alzheimer’s Disease (AD), structural details of misfolded Aβ(1–42) remain largely elusive. The neurotoxic amyloid proteins of Aβ(1–42) are found to have various morphologies, such as amyloid plaque, a hallmark of AD, which is depositions of tangled fibrillar aggregates, and non-fibrillar spherical assemblies, which usually display even higher neurotoxicity and different propagation features compared to that of Aβ(1–42) fibrils. Four divided parts on Aβ(1–42) fibrils and oligomers will be presented; the emphasis is given on structural studies, amyloid propagation features, relevance of various Aβ(1–42) amyloid aggregates to AD, and methodology development for structural studies of Aβ(1–42) amyloids. Part one illustrates the identification and structure elucidation of Aβ(1–42) seeded fibril. Part two describes the isolation of a spherical oligomer of Aβ(1–42) at a low temperature condition and subsequent structural conversion into amyloid fibril. Part three discusses cross-seeding between Aβ(1–40) and Aβ(1–42) prepared in vitro and seeding experiments with brain-Aβ-amyloid to prepare Aβ(1–42) fibrils replicated from Aβ amyloids derived from brain tissues. Lastly, Part four focuses on methodology development for bacterial overexpression of Aβ(1–42) and its applications in a structural elucidation.