Research Projects

Alzheimer’s disease (AD), the most common form of dementia, affects over 55 million people globally and presents a rising public health challenge, particularly in aging populations like India. Characterized by amyloid-β (Aβ) aggregation, oxidative stress, and neuronal degeneration, AD currently lacks disease-modifying therapies. A major pathological driver—Aβ-induced oxidative stress—is exacerbated by its interaction with redox-active metals like Cu and Fe, leading to uncontrolled generation of reactive oxygen species (ROS), mitochondrial dysfunction, and neuroinflammation. Conventional antioxidants fail to offer meaningful neuroprotection due to poor blood-brain barrier (BBB) penetration, limited stability, and stoichiometric ROS scavenging. This project proposes a novel, catalytic antioxidant strategy by developing corrole-based metallocomplexes incorporating transition metals such as Fe, Mn, and Cu. Corroles are trianionic macrocycles capable of stabilizing high-valent metal centers and enabling redox cycling, thus mimicking the activity of natural antioxidant enzymes. Preliminary data from our lab demonstrate that strategically modified metallocorroles cross the BBB, suppress ROS, inhibit Aβ42 aggregation, and restore neuronal integrity in both in vitro and in vivo AD models. The central hypothesis is that rationally designed metallocorroles can serve as multifunctional therapeutic agents that combine catalytic ROS decomposition, Aβ binding, and redox regulation, offering neuroprotection in AD. To test this, the project is structured into three phases: (i) synthesis of functionalized corrole ligands and metal complexes with tunable redox and biological properties; (ii) spectroscopic, electrochemical, and computational characterization to correlate structure with function; and (iii) biological evaluation in neuronal cultures and transgenic AD mouse models to assess efficacy in mitigating oxidative damage and cognitive decline. Key experiments include redox potential analysis via cyclic voltammetry, ROS scavenging assays, Thioflavin-T and TEM studies of Aβ aggregation, neuronal viability assays, and behavioral tests such as Y-maze and novel object recognition in 3×Tg-AD mice. In vivo BBB permeability and pharmacokinetic profiling will be confirmed by mass spectrometry and fluorescence imaging. If successful, this project will establish a new class of catalytic, disease-modifying therapeutics for AD, addressing the limitations of current treatments. It will advance fundamental understanding of redox-active macrocyclic complexes in biological systems and offer translational value through collaboration with biotech partners. The outcomes promise to strengthen India’s research leadership in neurotherapeutics and provide cost-effective solutions for neurodegenerative diseases.