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 (LGWE) is more potent in inhibiting Aβ peptide aggregation and defibrillation of Aβ40/Aβ42 aggregates. NMR studies showed that LGWE binds to the central hydrophobic area and C-terminal residues of Aβ40/Aβ42, thereby modulating the aggregation, and reducing cell membrane damage. Additionally, LGWE rescues Aβ toxicity in neuronal SH-SY5Y cells evident from decreases in ROS generation, membrane leakage, cellular apoptosis, and calcium dyshomeostasis. Notably, LGWE is non-toxic to neuronal cells and mouse models. Our study thus delves into the mechanistic insights of a repurposed drug LGWE with the potential to ameliorate Aβ induced neuroinflammation. [Display omitted] •Lasunadya Ghrita (LG), an Indian traditional medicine, can be repurposed to combat Alzheimer's disease.•LG water extracts were tested for inhibiting Aβ40/Aβ42 aggregation effective.•LG water extract inhibits amyloid beta aggregation and disintegrate mature fibrils into nontoxic species.•Bioactive compounds in LG water extract were found responsible for its anti-amyloidosis effects.•LG water extract strongly interacts with amyloid-prone region and C-terminal residues of Aβ40/Aβ42.•The LG water extract prevents Aβ40-induced cell death and neuronal apoptosis.