| Amyloid protein misfolding is a central pathological event in a spectrum of human age-related degenerative diseases including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, tauopathies, and spongiform encephalopathy. These dementias are widespread and affect billions of people worldwide. Although the specific amyloid protein involved in each of these diseases is different, amyloid proteins misfold through a common, conserved pathway to form highly-ordered, beta-sheet-rich fibrillar aggregates. Oligomeric intermediates assembled during this process represent the primary toxic neurotoxic species in many of these diseases. In AD, despite extensive research dedicated to unravel the mechanisms underlying Abeta oligomers' pathological role, the precise mechanisms remain unclear due to lack of detailed structural analysis. In this study, we investigated the causative link between the aberrant structures of protein oligomers and their toxic functions in disease pathogenesis. The data presented here reveal that soluble Abeta oligomers have complex structural polymorphism as evident by the immunological differences between prefibrillar and fibrillar conformations (Chapters Two and Three). Soluble Abeta fibrillar oligomers are rich in beta-sheets, on fibril-forming pathway and can eventually assemble into mature fibrils. In vitro, FOs propagate via an elongation, fragmentation, and replication mechanism that is similar to what is known for prion proteins. We also investigated the molecular mechanisms underlying FOs' pathological role in AD. The increased levels of FOs in AD patients, the tight correlation with the increased severity of dementia, and the structural similarity to fibrils present in amyloid plaques strongly suggest that FOs are highly pathological to AD. Through studies using rat hippocampal and cortical neurons, we found and confirmed that Abeta-mediated neurotoxicity is highly conformation dependent (Chapter Four). In the in vitro cell culture model, FOs induce neuronal toxicity by preferentially binding to a selective-population of stressed neurons at non-synaptic sites through their exposed hydrophobic surface. |
