Spectroscopic investigations on metal coordination to amyloid-β

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by progressive cognitive decline and neuronal loss. A key pathological hallmark of AD is the accumulation and aberrant aggregation of amyloid-beta (A beta) peptides, which contributes to synaptic dysfunction and neurotoxicity. While the aggregation behavior of A beta has been extensively studied, it can be altered by various factors, particularly metal ions, such as Fe(II/III), Cu(I/II), and Zn(II). These metal ions directly interact with specific amino acid residues in A beta, influencing its oligomerization, fibrillization, and capacity to generate reactive oxygen species, thereby exacerbating oxidative stress and accelerating disease progression. Understanding the coordination chemistry between metal ions and A beta is critical for deciphering their pathological impact in AD. This review provides a comprehensive overview of metal-bound A beta (metal-A beta) coordination at the molecular level, with a focus on insights gained from advanced spectroscopic methods. Nuclear magnetic resonance, electron paramagnetic resonance, and x-ray absorption spectroscopies collectively illuminate metal-binding sites, coordination geometries, and dynamic structural behavior of metal-A beta complexes. These complementary approaches enable detailed structural characterization and mechanistic understanding of metal-induced A beta aggregation and toxicity. By integrating spectroscopic findings on Fe(II/III), Cu(I/II), and Zn(II) coordination to A beta, we highlight their distinct roles in AD pathogenesis as well as the broader significance of metal-peptide interactions underlying the mechanisms of neurodegenerative diseases.