3؉ also inhibits fibril formation; however, the annular oligomers co-exist in the aggregation pathway. In conclusion, Zn 2؉ , Cu 2؉ , Fe 3؉ , and Al 3؉ adopt distinct folding and aggregation mechanisms to affect A, where A destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular A oligomer formation upon metal ion binding.
The brain deposition of amyloid plaques composed of A2 is the pathological hallmark of AD (1, 2). A is generated from sequential cleavages of amyloid precursor protein by -and ␥-secretases (3, 4). The predominant A isoforms are A40 and A42, which differ in two residues at the C terminus, where A42 is less abundant but more neurotoxic (5-8). A is a natively unfolded protein prone to aggregating into cross--amyloid fibrils through a nucleation-dependent polymerization pathway (9). A aggregation is considered the major culprit in AD, in which the A oligomers, but not fibrils, better correlate with cognitive impairment and synaptic dysfunction (10). A oligomers are referred to various different metastable intermediates found in the aggregation, including low molecular weight oligomers, spherical oligomers, A-derived diffusible ligands, globulomers, annular protofibrils, A56*, and curvilinear protofibrils (11)(12)(13)(14)(15)(16)(17)(18) (24 -25). These facts indicate that the elevation of the metal ions is relevant to AD pathology.A is able to bind to the metal ions (22, 23). A ion coordination, binding affinity, and induced aggregation have been studied intensively in various conditions; however, the results and mechanisms remain inconclusive. A-Cu 2ϩ coordination involves three intramolecular histidines (i.e. His-6, His-13, and His-14) in A (26 -28), with the fourth coordinate being either the amino group of the N terminus (29), an oxygen from Tyr-10 (30), or an oxygen from Glu-3 (29). The A-Zn 2ϩ complex is reportedly more complicated. A similar coordination with Cu 2ϩ has been proposed for Zn 2ϩ using the three histidines and the N terminus (31, 32). Both intermolecular A-Cu 2ϩ and A-Zn 2ϩ coordination have been reported via histidine bridges (28, 30 -33). Fe 3ϩ has also been shown to interact with histidines (37). Dissociation constants for the binding affinity of