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., Widera, D. ORCID: https://orcid.org/0000-0003-1686-130X, Dallas, M. ORCID: https://orcid.org/0000-0002-5190-0522 and Andrisano, V. (2019) Investigating in vitro amyloid peptide 1-42 aggregation: impact of higher molecular weight stable adducts. ACS Omega, 4 (7). pp. 12308-12318. ISSN 2470-1343 doi: 10.1021/acsomega.9b01531

Abstract/Summary

The self-assembly of amyloid peptides (Aβ), in particular Aβ1–42, into oligomers and fibrils is one of the main pathological events related to Alzheimer’s Disease (AD). Recent studies have demonstrated the ability of carbon monoxide releasing molecules (CORMs) to protect neurons and astrocytes from Aβ1-42 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 Aβ1–42, we studied the reactivity of CORM-2 and CORM-3 with Aβ1–42 in vitro and the potential inhibition of its aggregation by mass spectrometry (MS), as well as fluorescence and circular dichroism (CD) spectroscopies. The application of an electrospray ionisation-mass spectrometry (ESI-MS) method allowed the detection of stable Aβ1–42/CORMs adducts, involving the addition of the Ru(CO)2 portion of CORMs at histidine residues on the Aβ1-42 skeleton. Moreover, CORMs showed anti-aggregating properties through formation of stable adducts with Aβ1–42 as demonstrated by a thioflavin T (ThT) fluorescence assay and MS analysis. As a further proof, comparison of the CD spectra of Aβ1–42 recorded in the absence and in the presence of CORM-3 at 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 Aβ1–42 and CORMs, contributing new insights into the proposed neuroprotective mechanisms mediated by CORMs and disclosing a new strategy to divert amyloid aggregation and toxicity.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/84870
Identification Number/DOI	10.1021/acsomega.9b01531
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	ACS
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