Hierarchy and the mechanism of fibril formation in ADan peptides

Familial Danish dementia is a neurodegenerative disease which is a consequence of alterations in the BRI gene. The pathological signatures of the disease are cerebral amyloidolysis, parenchymal protein deposits and neuronal degeneration. Synthetic Danish dementia (ADan) peptides are capable of forming fibrillar assemblies in vitro at pH 4.8. However, the morphology of the aggregates formed depends greatly on the form of the peptides (oxidized or reduced). In addition to long slender assemblies (2-5 nm in diameter and several micrometers in length) we report ring-like or annular masses (8-9 nm in diameter and 1-2 mm in perimeter) in the case of the oxidized form of the peptides. The reduced forms mainly aggregate to produce granular heaps. The biophysical and kinetic characterization of the process of aggregation was carried out using different spectroscopic and imaging techniques. Neurotoxicity assays performed on both the forms reveal that the toxicity bears proportionality with the aggregate size.