Association between Alzheimer's Disease and Diabetes Mellitus-2: interaction between amyloid proteins, cellular toxicity and development of theranostic agents

• Grant number: 22/06637-0
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2023
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Biophysics - Radiology and Photobiology
• 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

Abstract

Patients with Alzheimer's disease (AD) present high risk of developing type II diabetes mellitus (TD2), and this has an impact on various sectors of our society. The heterogeneous aggregation between the proteins related to these diseases, ²A and hIAPP, has been proposed as a potential molecular mechanism. However, the structural characteristics of the aggregates generated from these interactions, their relationship with cellular toxicity, the damage caused to cell membranes, and how these phenomena are related to the association between AD and TD2 are fundamental issues still little explored. Another relevant issue regards the development of a strategy and/or compound that may potentialize the interactions with the target amino acids of these proteins, blocking aggregation and toxicity. This project aims to investigate, in real time, the aggregation process between ²A1-42 and hIAPP using spectroscopic techniques and bio-membrane models with the following objectives: (1) identify the experimental conditions that give rise to the toxic hybrid aggregates generated against human neuroblastoma cells SH-SY5Y and ²-cell models and the damage caused to normal and AD neuronal membrane models; (2) investigate the influence and effect of a third protein (albumin or insulin) on the interactions and toxicity of ²A/hIAPP aggregates. Develop new luminescent Ru(II) polypyridine complexes to (3) detect and differentiate the aggregated species, in real time, during heterogeneous aggregation since the early stages of aggregation as well as (4) inhibit the toxic aggregates by blocking the hIAPP and/or ²A aggregates by p-p-stacking and electrostatic interactions and hydrogen bonding between specific amino acids of proteins and the Ru(II) luminescent sensor.With this project, we intend to expand the investigations on the cellular toxicity of the ²A protein in AD that we have been carrying out in our laboratory for the heterogeneous ²A1-42 and hIAPP interactions and the correlations between AD and TD2.We strongly believe that these studies are essential to establish how these complex processes participate in the origin and progression of amyloid-related diseases and their associations in the development of new effective therapies against these diseases, as well as to open new research fronts for other amyloidogenic diseases. (AU)

Scientific publications

(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)

MARCHI, RAFAEL C.; KOCK, FLAVIO V. C.; DOS CAMPOS, ISABELE A. SOARES; JESUS, HUGO CESAR R.; VENANCIO, TIAGO; DA SILVA, MARIA FATIMA G. F.; FERNANDES, JOAO B.; ROLLINI, MANUELA; LIMBO, SARA; CARLOS, ROSE M.. Antioxidant activity of an Mg(ii) compound containing ferulic acid as a chelator: potential application for active packaging and riboflavin stabilisation. FOOD & FUNCTION, v. 15, n. 3, p. 12-pg., 2023-12-29. (22/06637-0, 18/16040-5)