Interaction of amyloid beta with humanin and acetylcholinesterase is modulated by ATP

• Published in: FEBS open bio 2020-12, Vol.10 (12), p.2805-2823
• Main Authors: Atali, Sarah, Dorandish, Sadaf, Devos, Jonathan, Williams, Asana, Price, Deanna, Taylor, Jaylen, Guthrie, Jeffrey, Heyl, Deborah, Evans, Hedeel Guy
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Alzheimer's disease; Amino acids; amyloid‐beta; Aqueous solutions; Conformation; Cytotoxicity; Fibrils; Heparan sulfate; Humanin; Intracellular; Intracellular signalling; kinetics; Lung cancer; Monomers; Neurodegenerative diseases; Non-small cell lung carcinoma; p53 Protein; peptide interaction; Peptides; Phosphorylation; Physiology; Purine receptors; Toxicity
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13023

Both HN and AChE can bind Aβ in the absence of added ATP. Addition of ATP increases the binding affinity of Aβ to HN but not to AChE. Humanin (HN) is known to bind amyloid beta (Aβ)‐inducing cytoprotective effects, while binding of acetylcholinesterase (AChE) to Aβ increases its aggregation and cytotoxicity. Previously, we showed that binding of HN to Aβ blocks aggregation induced by AChE and that HN decreases but does not abolish Aβ‐AChE interactions in A549 cell media. Here, we set out to shed light on factors that modulate the interactions of Aβ with HN and AChE. We found that binding of either HN or AChE to Aβ is not affected by heparan sulfate, while ATP, thought to reduce misfolding of Aβ, weakened interactions between AChE and Aβ but strengthened those between Aβ and HN. Using media from either A549 or H1299 lung cancer cells, we observed that more HN was bound to Aβ upon addition of ATP, while levels of AChE in a complex with Aβ were decreased by ATP addition to A549 cell media. Exogenous addition of ATP to either A549 or H1299 cell media increased interactions of endogenous HN with Aβ to a comparable extent despite differences in AChE expression in the two cell lines, and this was correlated with decreased binding of exogenously added HN to Aβ. Treatment with exogenous ATP had no effect on cell viability under all conditions examined. Exogenously added ATP did not affect viability of cells treated with AChE‐immunodepleted media, and there was no apparent protection against the cytotoxicity resulting from immunodepletion of HN. Moreover, exogenously added ATP had no effect on the relative abundance of oligomer versus total Aβ in either cell line.