Amyloid protein aggregates and the relationship between Alzheimer's Disease and type 2 Diabetes investigated by Ru(II) luminescent complexes

• Grant number: 19/21143-0
• Support Opportunities: Regular Research Grants
• Duration: March 01, 2020 - February 28, 2022
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Rose Maria Carlos
• Grantee: Rose Maria Carlos
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated researchers: Elaine Guadelupe Rodrigues

Abstract

The aggregation processes of amyloid protein have implications in a number of diseases, including amyloid beta peptide (Ab) in Alzheimer's disease (AD) and insulin in type 2 diabetes. In addition to being costly chronic diseases included in the list of leading causes of death, several studies have indicated a close relationship between them, such as resistance to insulin, which is the reason why AD has been described as type 3 diabetes. Among the various species of Ab, the oligomeric species (OAb) is considered to be the most toxic to AD. These species are generated in the early stages of aggregation by combining dimers, trimers, and even dodecamers of Ab. Thus the composition, conformation and size of the OAb that determine the risks in AD have not yet been elucidated. Other relevant issues, such as the interaction of OAb with cell membrane, which is considered responsible for CNS synaptic loss causing cognitive changes that underlie AD, and the protective effect of insulin on OAb toxicity, are also not clear yet. Since all of these characteristics have the potential to alter the major aggregation properties of Ab, it is important that the effects on these factors be investigated. One of the major challenges in amyloid protein research is to find a sensitive and selective strategy for species generated in the early stages of aggregation. Recent studies conducted in our laboratory have shown that the Ru(II) luminescent complexes developed by us are Ab-sensitive molecular probes. These complexes are able to identify and differentiate Ab aggregates by changes in luminescent responses without changing the intrinsic emission of Ab: Ab1-28 (1.7 and 18.5 ns), Ab11-22 (1.8 and 22.8 ns), and Ab1-40 (2.8 and 7.4 ns). These results motivated our research group to intensify the studies on amyloid proteins. In this project, we intend to carry out a comparative study of OAb and toxicity with the following peptides: Ab (1-28, 29-40, 25-35, 1-40, 1-42) and p3 (17-40, 17-42 ), which are the species most commonly identified in vitro and produced in vivo by Ab. We also intend to investigate the influence and effect of cell membrane and insulin on the conformation and toxicity of these species. The aggregation of Ab in real time will be monitored by direct observation of morphological changes of the aggregates by electron microscopy (MET and CryoEM) and by intrinsic emission of Ab. Indirectly, the aggregation will be monitored by changes in the intensity and emission lifetime of the Ru(II) complexes and by confocal fluorescence microscopy. OAb toxicity will be investigated through changes in viability of PC12 neuronal cells. (AU)

Scientific publications

(6)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PEREIRA, LORENA M. B.; CALI, MARIANA P.; MARCHI, RAFAEL C.; PAZIN, WALLANCE M.; CARLOS, ROSE M.. Luminescent imaging of insulin amyloid aggregation using a sensitive ruthenium-based probe in the red region. Journal of Inorganic Biochemistry, v. 224, NOV 2021. (20/12129-1, 19/21143-0, 17/00839-1)

SILVA, ELDEVAN; MARCHI, RAFAEL; MATOS, CARLA; SILVA, MARIA; FERNANDES, JOAO; BUENO, ODAIR; CARLOS, ROSE. INSECTICIDAL AND FUNGICIDAL ACTIVITY OF A MAGNESIUM COMPOUND CONTAINING ISOVANILLIC ACID AGAINST LEAF-CUTTING ANT AND ITS SYMBIOTIC FUNGUS. Química Nova, v. 44, n. 3, p. 267-271, 2021. (18/16040-5, 13/05536-6, 17/00839-1, 18/09145-5, 15/23146-6, 17/15455-4, 19/21143-0)

MARCHI, RAFAEL C.; CAMPOS, ISABELE A. S.; SANTANA, VINICIUS T.; CARLOS, ROSE M.. Chemical implications and considerations on techniques used to assess the in vitro antioxidant activity of coordination compounds. Coordination Chemistry Reviews, v. 451, JAN 15 2022. (18/03424-0, 19/21143-0)

CALI, MARIANA P.; PEREIRA, LORENA M. B.; TEODORO, MARCIO D.; SELLANI, TARCISO A.; RODRIGUES, ELAINE G.; CARLOS, ROSE M.. Comparison of A beta (1-40, 1-28, 11-22, and 29-40) aggregation processes and inhibition of toxic species generated in early stages of aggregation by a water-soluble ruthenium complex. Journal of Inorganic Biochemistry, v. 215, FEB 2021. (19/21143-0, 17/00839-1)

MARCHI, RAFAEL C.; AGUIAR, INARA; CAMILO, MARIANA R.; BRAGA, ADRIANO H.; DO NASCIMENTO, EDUARDO S. P.; SANTANA, VINICIUS T.; NASCIMENTO, OTACIRO R.; CARLOS, ROSE M.. Photochemical Properties of a Mononuclear Mn(I) Triscarbonyl Complex in Water: An Insight into Different Oxidation States. CHEMISTRYSELECT, v. 6, n. 33, p. 8746-8753, SEP 7 2021. (19/21143-0, 11/06244-3, 14/12538-8)

ALMEIDA, MARLON P.; KOCK, FLAVIO V. C.; DE JESUS, HUGO C. R.; CARLOS, ROSE M.; VENANCIO, TIAGO. Probing the acetylcholinesterase inhibitory activity of a novel Ru(II) polypyridyl complex and the supramolecular interaction by (STD)-NMR. Journal of Inorganic Biochemistry, v. 224, NOV 2021. (18/09145-5, 18/16040-5, 19/21143-0)