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.

ABSTRACT: The self-association of amyloid-β (Aβ) peptide into neurotoxic oligomers is believed to be central to Alzheimer's disease (AD). Copper is known to impact Aβ 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 Aβ40 and Aβ42 isoforms. Globally fitting microscopic rate constants for fibril assembly indicates copper will accelerate fibril formation of Aβ40 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 Aβ42 as prefibrillar oligomers and curvilinear protofibrils. Remarkably, the Cu(II) addition to preformed Aβ42 fibrils causes the disasse

SUBMITTER: Tian Y 

PROVIDER: S-EPMC10900208 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature