Enhancing amyloid beta inhibition and disintegration by natural compounds: A study utilizing spectroscopy, microscopy and cell biology

Amyloid proteins and peptides play a pivotal role in the etiology of various neurodegenerative diseases, including Alzheimer's disease (AD). Synthetically designed small molecules/ peptides/ peptidomimetics show promise towards inhibition of various kinds of amyloidosis. However, exploration of compounds isolated from natural extracts having such potential is lacking. Herein, we have investigated the repurposing of a traditional Indian medicine Lasunadya Ghrita (LG) in AD. LG is traditionally used to treat gut dysregulation and mental illnesses. Various extracts of LG were obtained, characterized, and analyzed for inhibition of Aβ aggregation. Biophysical studies show that the water extract of LG (LG_WE) is more potent in inhibiting Aβ peptide aggregation and defibrillation of Aβ40/Aβ42 aggregates. NMR studies showed that LG_WE binds to the central hydrophobic area and C-terminal residues of Aβ40/Aβ42, thereby modulating the aggregation, and reducing cell membrane damage. Additionally, LG_WE rescues Aβ toxicity in neuronal SH-SY5Y cells evident from decreases in ROS generation, membrane leakage, cellular apoptosis, and calcium dyshomeostasis. Notably, LG_WE is non-toxic to neuronal cells and mouse models. Our study thus delves into the mechanistic insights of a repurposed drug LG_WE with the potential to ameliorate Aβ induced neuroinflammation.