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Influence of biomolecules on the development of Alzheimer Disease and theranostic effect of the [Ru(phen)2(pNDIp)](PF6)2 complex.

Grant number: 23/02083-2
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2023
Effective date (End): February 28, 2025
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
Principal Investigator:Rose Maria Carlos
Grantee:Bárbara Patrícia Neves Silva
Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil


Alzheimer's disease (AD) is characterized by the progressive loss of neurological functions such as loss of recent memory and degeneration of neuronal tissues and the formation of senile plaques mainly by the accumulation of amyloid beta peptide (A²) in the brain. A² aggregates are formed both by aggregation and homogeneous fibrillation of A², as well as by heterogeneous interactions between A²and different biomolecules such as the enzyme glyceraldehyde-3-phosphate dehydrogenase (GADPH) and the natural steroid cholesterol (Cho). On the other hand, human albumin (HSA) is described as a regulator of amyloid fibrillation (A²). When considering these results, it is important to emphasize the studies indicating that GADPH and Cho suppress the ability of HSA to inhibit the formation of A² fibers. However, the elucidation of the kinetic profile of aggregation and toxicity underlying these effects have not yet been clarified, nor the limit quantity for these interventions.In this present work we intend to intensify these studies following in vitro the kinetic profiles of homogeneous (A²1-42 and HSA) and heterogeneous (A²1-42: GADPH, A²1-42:Cholesterol, A²1-42:HSA) aggregation, determining the detection limit, dissociation constant and stoichiometry of the interaction between A² (monomer and fibrils) and GADPH, Cho and HSA; to explore the mechanism involving the suppressor effect of HSA inhibition for A² against GADPH and Cho, and the cytotoxicity between the different interactions against the neuronal cell line SH-SY5Y. There is no cure for AD. Therefore, the development of new non-toxic compounds that interfere with A²fibrillation are promising strategies for the elucidation of the aggregation mechanism and treatment for AD. Our research group has its projects directed towards this strategy. For this, in this work we intend to use the luminescent properties of the new complex [Ru(phen)2(pNDIp)](PF6)2, (RupNDIp), prepared in our laboratory, to map by luminescent image the species generated during the initial stages of aggregation homogeneous and heterogeneous A² proposed in this work and toxicity. If the results obtained in this work in the presence of the RupNDIp complex are promising in vitro, we intend to perform these in vivo in a next stage and evaluate the best route of administration of this complex in models of wild-type and transgenic AD mice (2xTgAD and 5xTgAD).

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