Dual Modification of Amyloid- Peptides by a Mononuclear Cobalt Complex and O2

07 July 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Alzheimer’s disease (AD) is the most common form of dementia that affects millions of people worldwide. The hallmark of this disease is the accumulation of amyloid-beta (Abeta) aggregates that lead to neuronal death and cognitive defects. Various chemical reagents, including transition metal complexes, have been developed to change Abeta peptides with the consequent impact on their aggregation profiles; however, the examples of Abeta modifications by transition metal complexes are very limited. Here we report, for the first time, the site-specific modifications of Abeta peptides using a mononuclear cobalt complex, [CoII(TBDAP)(H2O)(NO3)](NO3) (Co(II)(TBDAP); TBDAP = N,N-di-tert-butyl-2,11-diaza[3.3](2,6)-pyridinophane). Co(II)(TBDAP) can induce modifications onto Abeta peptides, including decarboxylation and deamination, fragmentation, and a combination of both. Our spectrometric and spectroscopic studies manifest that the oxidation of the Co(II) center to Co(III) by O2 is a crucial step for inducing these modifications, which is further supported based on the reactivities of a newly synthesized Co(III) complex, [CoIII(TBDAP)(Cl)2](NO3) (Co(III)(TBDAP)), towards Abeta peptides. Such modifications onto Abeta by Co(II)(TBDAP) can redirect its on-pathway aggregation to off-pathway, yielding relatively less toxic short fibrils or amorphous aggregates. Our work provides valuable insights into the distinct reactivities of cobalt complexes towards Abeta peptides, which offers a novel strategy to control Abeta amyloidogenesis using transition metal complexes.

Keywords

Transition metal complexes
Modifications of Abeta peptides
Alzheimer's disease
Control of Abeta amyloidogenesis

Supplementary materials

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Supporting Information
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Experimental, Tables S1 and S2, and Figures S1-S9
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