Cyclic undecapeptide Cyclosporin A mediated inhibition of amyloid synthesis: Implications in alleviation of amyloid induced neurotoxicity

Abstract

Amyloids are highly organized fibril aggregates arise from inappropriately folded form of the protein or polypeptide precursors under both physiological as well as simulated ambience. Amyloid synthesis is a multistep process that involves formation of several metastable intermediates. Among various intermediate species, the as-formed soluble oligomers are extremely toxic to the neuronal cells. In the present study, we evaluated cyclosporine A (CsA), an undecapeptide, for its potential to prevent aggregation of model protein ovalbumin (OVA). In an attempt to elucidate involved operative mechanism, the preliminary studies delineate that CsA affects both primary nucleation as well as other secondary pathways involved in OVA fibrillation process. By its specific interaction with amyloid intermediates, the cyclic peptide CsA seems to regulate the lag phase of the fibrillation process in concentration dependent manner. The present study further suggests that exposure to CsA during lag phase ensues in reversal of OVA fibrillation process. On the contrary, mature OVA fibril remained impervious to the CsA treatment. The cyclic undecapeptide CsA was also found to successfully alleviate amyloid induced toxicity in neuroblastoma cells.

Exploratory Analysis of iPSCS-Derived Neuronal Cells as Predictors of Diagnosis and Treatment of Alzheimer Disease

“…This is in line with recent data from Stallings' group, showing that cyclosporine-a blocked dendritic spine loss in Aβ42-treated cells [53]. Furthermore, cyclosporine-a inhibited amyloid synthesis and improved amyloid induced neurotoxicity in neuroblastoma cells [54]. Finally, a pilot open-label study of tacrolimus, which shares the same mode of action with cyclosporin-a in AD (ClinicalTrials.gov Identifier: NCT04263519) is expected to be completed by December 2021.…”

Potential Protective Function of Aβ42 Monomer on Tauopathies

“…Recently, it has been reported that CycA, an 11-residue macrocyclic peptide, can interact with amyloids to inhibit fibrillation and alleviate amyloid-induced toxicity in neuroblastoma cells. 31 Kazmi et al proposed one of the potential mechanisms in which this inhibition of fibrillation may occur through the binding of CycA with amyloidogenic protein monomers or oligomeric intermediates. 31 We used IMS-MS to explore the two above hypotheses.…”

“…31 Kazmi et al proposed one of the potential mechanisms in which this inhibition of fibrillation may occur through the binding of CycA with amyloidogenic protein monomers or oligomeric intermediates. 31 We used IMS-MS to explore the two above hypotheses. Because CycA is lipophilic, we observed the complexes of CycA with both Tau and Aβ (Figure S9).…”

Bioavailability and Health Impact of Ingested Amyloid‐like Protein Fibrils and their Link with Inflammatory Status: A Need for More Research?

“…[ 17 ] In contrast to what was observed for the intestinal cell line, cytotoxicity was observed for the neuronal SH‐SY5Y cell line upon treatment with prefibrillar OVA aggregates (1 mg mL –1 ). [ 18 ] This illustrates another topic of debate: the cytotoxic form of amyloids. For long, it was believed that mature AFs and plaques of endogenous proteins were the cause of tissue damage and neurodegeneration, [ 19 ] but more recent evidence suggests that oligomers and prefibrillar aggregates are the main mediators of amyloid toxicity.…”