Controlling Amyloid-¿ Aggregation through Photoactive Ru(II) Complexes

• Grant number: 25/07883-2
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: August 01, 2025
• End date: January 31, 2026
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Rose Maria Carlos
• Grantee: Ana Carla Candido da Silva
• Supervisor: Tim Storr
• Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Institution abroad: Simon Fraser University, Burnaby, Canada
• Associated to the scholarship: 23/17575-8 - Investigation of peptide-peptide interactions site using the photochemical and photophysical properties of the cis-[Ru(dmphen)2(Aepy)2]2+ luminescent complex, BP.MS

Abstract

Alzheimer's disease (AD), the most common form of dementia, is a devastatingneurodegenerative disease and a major concern for global public health systems. Itspathological hallmark is senile plaques, primarily formed by the aggregation of the betaamyloid (A¿) peptide. While the importance of A¿1-42 aggregates in AD's molecularetiology is well recognized, the amino acid sequence responsible for aggregation remainsunclear. Several studies indicate that the hydrophobic regions of A¿ are the most prone toaggregation and fibrillogenesis, but the molecular mechanism of these interactions hasnot yet been defined. On the other hand, several articles suggest that electrostaticinteractions stabilize the structure for hydrogen bonding, strengthening the antiparallelarrangements for aggregation. Therefore, determining the interaction sites of A¿ is not atrivial process. As a result, there is growing interest in understanding the molecularmechanisms of A¿ aggregation to mitigate the detrimental effects of A¿ toxic species onthe disease. Recently, we have demonstrated that the luminescent cis-[Ru(phen)2(Aepy)]2+ complex (RuApy, phen = 1,10-phenanthroline, Aepy= 4-(2-aminoethyl) pyridine) prepared in our laboratory interacts with A¿1-42 enabling themonitoring of A¿ aggregation. Furthermore, the RuAepy is phototoactive toward Aepyrelease generating the aquo complex cis-[Ru(phen)2(H2O)2]2+ a feature that allows one totrack the species generated during A¿ aggregation and regenerate the luminescence. Inthis project, we aim to further investigate the molecular binding sites of A¿ that definethe interactions between the peptide chains and the RuAepy complex. Additionally, wewill explore how the photoactivation of RuAepy influences the aggregation process ofA¿.Here in, with the aid of 1H NMR, ESI mass spectrometry, gel electrophoresis,Western blotting techniques, and transmission electron microscopy (TEM) we intend tosystematically study the interaction between the RuAepy complex and the A¿ peptideand how photoactivation of Ru(II) Complexes can modulate the aggregation process : APhotochemical Approach to its photoproducts with A¿1-42, A¿21-40 and A¿1-28.Detailed information on the molecular level of how the RuAepy affects theaggregation and toxicity of the hydrophobic and hydrophilic regions of A¿ are exploredin this project. These studies could contribute to the elucidation of A¿ aggregation andtoxicity and to the development of new anti-amyloid therapies for Alzheimer's disease. (AU)