title: Role of norepinephrine in Aβ-related neurotoxicity: dual interactions with Tyr10 and SNK(26-28) of Aβ.
abstract: With their capability to inhibit the formation of amyloid-β peptide (Aβ) fibril, norepinephrine (NE), and other catechol derivatives have been considered for the potential treatment of Alzheimer's disease (AD). Such treatment, however, remains debatable because of the diverse functions of Aβ and NE in AD pathology. Moreover, the complicated oxidation accompanying NE has caused the majority of the previous research to focus on the binding of NE oxides onto Aβ. The molecular mechanism by which Aβ interacts with the reduction state of NE, which is correlated with the brain function, should be urgently explored. In this work, by controlling rigorous anaerobic experimental conditions, the molecular mechanism of the Aβ/NE interaction was investigated, and two binding sites were revealed. Tyr10 was identified as the strong binding site of NE, and SNK(26-28) segment was the weak binding segment. Furthermore, thioflavin T fluorescence confirmed NE's positive function of inhibiting Aβ aggregation through its weak binding with SNK(26-28) segment. Meanwhile, 7-OHCCA fluorescence exhibited NE's negative function of enhancing ·OH generation through inhibiting the Aβ/Cu2+ coordination. The viability tests of the neuroblastoma SH-SY5Y cells displayed that the coexistence of NE, Cu2+, and Aβ induced lower cell viability than free Cu2+, indicating the significant negative effect of excessive NE on AD progression. These data revealed the possible pathway of NE-induced damage in AD brain, which is significant for understanding the function of NE in Aβ-involved AD neuropathology and for designing an NE-related therapeutic strategy for AD.
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Liu
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Wan
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Bin
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xiang
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D009447:Neuroblastoma / Q000473:pathology; D009638:Norepinephrine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D020349:Surface Plasmon Resonance; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014443:Tyrosine; D003300:Copper; D009638:Norepinephrine
keywords: amyloid-β peptide; binding; cytotoxicity; fibril; norepinephrine