Invited Talk 21st International Conference on Biological Inorganic Chemistry 2025

Transition metal ions, particularly copper, are indispensable components in the biological system, playing crucial roles in various cellular processes such as antioxidant defense, neurotransmitter biosynthesis, and energy metabolism, owing to their inherent redox activity. Dysregulation of copper homeostasis is intrinsically linked to the onset of copper metabolism disorders, cancers, and neurodegenerative disorders.^1,2 In this presentation, I introduce a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to amyloid-β (Aβ), a primary pathological factor of Alzheimer’s disease.³ Our work demonstrates an effective approach to modifying Cu(II) coordination sphere in Aβ via copper–O2 chemistry, which can alter the coordination, aggregation, and toxicity profiles of Cu(I/II)–Aβ complexes. Furthermore, I present the discovery involving the conformational and functional changes of a native neuropeptide somatostatin (SST) in the presence of copper ions.⁴ Cu(II) was shown to induce the self-assembly of SST, impeding its binding to the receptor. Remarkably, SST reciprocally modifies the aggregation pathways of metal–Aβ species, unexpectedly mitigating their cytotoxicity and interactions with cell membranes. Our findings shed light on the functional switching of SST from a neurotransmitter to a modulatory function against Aβ-mediated toxicity upon disturbance of copper homeostasis.