The self-assembly of amyloid peptides (A beta), in particular A beta(1-42), into oligomers and fibrils is one of the main pathological events related to Alzheimer's disease. Recent studies have demonstrated the ability of carbon monoxide-releasing molecules (CORMs) to protect neurons and astrocytes from A beta(1-42) toxicity. In fact, CORMs are able to carry and release controlled levels of CO and are known to exert a wide range of anti-inflammatory and anti-apoptotic activities at physiologically relevant concentrations. In order to investigate the direct effects of CORMs on A beta(1-42), we studied the reactivity of CORM-2 and CORM-3 with A beta(1-42) in vitro and the potential inhibition of its aggregation by mass spectrometry (MS), as well as fluorescence and circular dichroism spectroscopies. The application of an electrospray ionization-MS (ESI-MS) method allowed the detection of stable A beta(1-42)/CORMs adducts, involving the addition of the Ru(CO)(2) portion of CORMs at histidine residues on the A beta(1-42) skeleton. Moreover, CORMs showed anti-aggregating properties through formation of stable adducts with A beta(1-42) as demonstrated by a thioflavin T fluorescence assay and MS analysis. As further proof, comparison of the CD spectra of A beta(1-42) recorded in the absence and in the presence of CORM-3 at a 1: 1 molar ratio showed the ability of CORM-3 to stabilize the peptide in its soluble, unordered conformation, thereby preventing its misfolding and aggregation. This multi-methodological investigation revealed novel interactions between A beta(1-42) and CORMs, contributing new insights into the proposed neuroprotective mechanisms mediated by CORMs and disclosing a new strategy to divert amyloid aggregation and toxicity.

De Simone A., Naldi M., Tedesco D., Milelli A., Bartolini M., Davani L., et al. (2019). Investigating in vitro amyloid peptide 1−42 aggregation: Impact of higher molecular weight stable adducts. ACS OMEGA, 4(7), 12308-12318 [10.1021/acsomega.9b01531].

Investigating in vitro amyloid peptide 1−42 aggregation: Impact of higher molecular weight stable adducts

De Simone A.;Naldi M.;Tedesco D.;Milelli A.;Bartolini M.;Davani L.;Andrisano V.
2019

Abstract

The self-assembly of amyloid peptides (A beta), in particular A beta(1-42), into oligomers and fibrils is one of the main pathological events related to Alzheimer's disease. Recent studies have demonstrated the ability of carbon monoxide-releasing molecules (CORMs) to protect neurons and astrocytes from A beta(1-42) toxicity. In fact, CORMs are able to carry and release controlled levels of CO and are known to exert a wide range of anti-inflammatory and anti-apoptotic activities at physiologically relevant concentrations. In order to investigate the direct effects of CORMs on A beta(1-42), we studied the reactivity of CORM-2 and CORM-3 with A beta(1-42) in vitro and the potential inhibition of its aggregation by mass spectrometry (MS), as well as fluorescence and circular dichroism spectroscopies. The application of an electrospray ionization-MS (ESI-MS) method allowed the detection of stable A beta(1-42)/CORMs adducts, involving the addition of the Ru(CO)(2) portion of CORMs at histidine residues on the A beta(1-42) skeleton. Moreover, CORMs showed anti-aggregating properties through formation of stable adducts with A beta(1-42) as demonstrated by a thioflavin T fluorescence assay and MS analysis. As further proof, comparison of the CD spectra of A beta(1-42) recorded in the absence and in the presence of CORM-3 at a 1: 1 molar ratio showed the ability of CORM-3 to stabilize the peptide in its soluble, unordered conformation, thereby preventing its misfolding and aggregation. This multi-methodological investigation revealed novel interactions between A beta(1-42) and CORMs, contributing new insights into the proposed neuroprotective mechanisms mediated by CORMs and disclosing a new strategy to divert amyloid aggregation and toxicity.
2019
De Simone A., Naldi M., Tedesco D., Milelli A., Bartolini M., Davani L., et al. (2019). Investigating in vitro amyloid peptide 1−42 aggregation: Impact of higher molecular weight stable adducts. ACS OMEGA, 4(7), 12308-12318 [10.1021/acsomega.9b01531].
De Simone A.; Naldi M.; Tedesco D.; Milelli A.; Bartolini M.; Davani L.; Widera D.; Dallas M.L.; Andrisano V.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/702795
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