Copper(II) Can Kinetically Trap Arctic and Italian Amyloid-β40 as Toxic Oligomers, Mimicking Cu(II) Binding to Wild-Type Amyloid-β42: Implications for Familial Alzheimer's Disease

The self-association of amyloid-beta (A beta) peptide into neurotoxic oligomers is believed to be central to Alzheimer's disease (AD). Copper is known to impact A beta assembly, while disrupted copper homeostasis impacts phenotype in Alzheimer's models. Here we show the presence of substoichiometric Cu(II) has very different impacts on the assembly of A beta 40 and A beta 42 isoforms. Globally fitting microscopic rate constants for fibril assembly indicates copper will accelerate fibril formation of A beta 40 by increasing primary nucleation, while seeding experiments confirm that elongation and secondary nucleation rates are unaffected by Cu(II). In marked contrast, Cu(II) traps A beta 42 as prefibrillar oligomers and curvilinear protofibrils. Remarkably, the Cu(II) addition to preformed A beta 42 fibrils causes the disassembly of fibrils back to protofibrils and oligomers. The very different behaviors of the two A beta isoforms are centered around differences in their fibril structures, as highlighted by studies of C-terminally amidated A beta 42. Arctic and Italian familiar mutations also support a key role for fibril structure in the interplay of Cu(II) with A beta 40/42 isoforms. The Cu(II) dependent switch in behavior between nonpathogenic A beta 40 wild-type and A beta 40 Arctic or Italian mutants suggests heightened neurotoxicity may be linked to the impact of physiological Cu(II), which traps these familial mutants as oligomers and curvilinear protofibrils, which cause membrane permeability and Ca(II) cellular influx.