Disulfide-rich, cyclic peptides fromClitoria ternateaprotect against β-amyloid toxicity and oxidative stress in transgenicCaenorhabditis elegans

Abstract

Neurotoxic aggregation of (Aβ) amyloid peptide is a hallmark of Alzheimers disease and increased reactive oxygen species (ROS) is known to be associated with this. Here, we report neuroprotective effects of disulfide-rich, circular peptides from Clitoria ternatea on Aβ induced toxicity in transgenic Caenorhabditis elegans. We show that cyclotide rich fractions from different plant tissues delay Aβ-induced paralysis in transgenic CL4176 strain expressing human muscle specific Aβ1-42 gene. It also improved Aβ induced defects in chemotaxis in CL2355 expressing Aβ1-42 in neuronal cells. ROS assay suggests that this is likely mediated by inhibition of Aβ oligomerization. Further, Aβ deposits were reduced in the strain, CL2006 treated with the fractions. Computational docking and molecular dynamics (MD) simulation support the findings since cyclotides bind effectively and stably to different forms of Aβ structures via hydrogen bonding and hydrophobic interactions. MD simulation further shows that cyclotides destabilize toxic amyloid assemblies. The study shows that cyclotides from C. ternatea could be a source of novel pharmacophore scaffold against neurodegenerative diseases.

Exendin-4 alleviates β-Amyloid peptide toxicity via DAF-16 in a Caenorhabditis elegans model of Alzheimer's disease

“…As we all know, ROS played a negative role in longevity (Sanz, 2016;Dilberger et al, 2019;Huang et al, 2021) and paralysis (Tang et al, 2022), and the aggregation of Aβ (1-42) will lead to the accumulation of ROS, which will affect the onset of paralysis and life span (Ewald, 2018;Kalmankar et al, 2021). Our results showed that exendin-4 reduced ROS, which was beneficial to prolong life and improve paralysis.…”

Carnosic acid ameliorated Aβ-mediated (amyloid-β peptide) toxicity, cholinergic dysfunction and mitochondrial defect in Caenorhabditis elegans of Alzheimer's Model

“…The CI was used to determine the proportion of worms that arrived at the quadrants containing attractants and to assess chemotaxis behavior. 45 After the treatment, a significant decrease in CI was displayed in transgenic strain CL2355 as compared to the control strain CL2122 (Fig. 4B, p < 0.05).…”

“…6E and F, in the control group, the in vivo ROS were at a high level, consistent with the phenomenon that Aβ could mediate the abnormal accumulation of ROS. 8,45 The ROS levels and MDA content of CL4176 and CL2006 were significantly reduced in the CA treatment group, indicating that CA was capable of decreasing ROS levels and reducing lipid peroxidation (Fig. 6E-H, p < 0.05).…”

“…human Aβ 1-42 in neuronal cells, leading to chemotaxis dysfunction, and could simulate the aggregation of Aβ 1-42 in AD brains. 45 Hence, the CL2355 and its control strain CL2122 were investigated to explore whether CA could protect neurons from Aβ-induced toxicity. The CI was used to determine the proportion of worms that arrived at the quadrants containing attractants and to assess chemotaxis behavior.…”

Effects of a plant cyclotide on conformational dynamics and destabilization of β-amyloid fibrils through molecular dynamics simulations

“…Similarly, Wang and co-workers demonstrated that naturally occurring cyclic peptides, sunflower trypsin inhibitor 1 (SFTI-1) and the cyclotide kB1, have an inherent ability to inhibit tau fibril growth and aggregation, specifically the AcPHF6-a tau-derived peptide (Wang et al, 2016). Our group recently demonstrated the in vivo anti-Aβ effects of cyclotides, purified from a Indian medicinal plant Clitoria ternatea, using three transgenic Caenorhabditis elegans models that exhibits pathological behaviours associated with Aβ (Kalmankar et al, 2021). We described a novel neuroprotective activity of cyclotides against Aβ-induced toxicity indicating that these could be potential therapeutic leads for blocking the progression of AD.…”