Small Molecules with Cyclic Dipeptide and Gallic Acid Moieties Ameliorate Ferroptosis and Amyloid Toxicity Associated with Alzheimer’s Disease — ASN Events
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  3. Small Molecules with Cyclic Dipeptide and Gallic Acid Moieties Ameliorate Ferroptosis and Amyloid Toxicity Associated with Alzheimer’s Disease

Small Molecules with Cyclic Dipeptide and Gallic Acid Moieties Ameliorate Ferroptosis and Amyloid Toxicity Associated with Alzheimer’s Disease (#329)

Dikshaa Padhi 1 , Prayasee Baruah 1 , Madhu Ramesh 1 , Hariharan Moorthy 1
  1. JAWAHARLAL NEHRU CENTRE FOR ADVANCED SCIENTIFIC RESEARCH (JNCASR), Bengaluru, BENGALURU, NON-US/NON-CANADIAN, India

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of insoluble amyloid plaques (Aβ42) and neurofibrillary tangles (NFTs). However, NFTs are composed of tau protein which is thought to be mediated by the formation of liquid-liquid phase separation (LLPS), which often grows and matures to form NFTs. In the context of AD, ferroptosis, a type of cell death that is dependent on iron and lipid peroxidation, marks a major event in the pathological cascade of AD. The major hallmarks of ferroptosis include excessive iron accumulation, heightened lipid peroxidation, generation of reactive oxygen species (ROS), and mitochondrial damage. Importantly, excessive ROS can inactivate or degrade GPX4 levels, leading to ferroptosis. Herein, we have rationally designed and synthesized cyclic dipeptides (CDPs) with gallic acid moieties and evaluated their potency as inhibitors of ferroptosis and amyloid toxicity in AD. Experimental studies transcend GCTR as an effective modulator of Fe-induced Aβ toxicity, ROS generation, and mitochondrial and neuronal damage. Interestingly, we report for the first time GCTR as a synthetic small molecule that restores GPX4 activity and enhances its intrinsic cellular levels, thus targeting the GPX4-ferroptosis axis. Moreover, GCTR has been shown to act as a potent modulator of tau aggregation, wherein the plausible mechanism of action (MOA) has been elucidated to work by prevention of Fe-driven tau LLPS. Indeed, this is believed to be the first report of a synthetic small molecule-based dual modulator of ferroptosis and amyloid toxicity in the context of AD. However, the findings of this study provide a strong foundation for future research on GCTR as a potential treatment for AD, whilst facilitating the design of small-molecule-based therapeutics for dual targeting of ferroptosis and amyloid toxicity in AD.64c3ff387fdef-Figure.png

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