Complicated function of dopamine in Aβ-related neurotoxicity: Dual interactions with Tyr10and SNK(26-28) of Aβ.
With the capability to inhibit the formation of amyloid β peptides (Aβ) fibril, dopamine (DA) 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 DA in AD pathology. Moreover, the complicated oxidation accompanying DA has caused the majority of the previous research to focus on the binding of DA oxides onto Aβ. The molecular mechanism by which Aβ interacts with the reduction state of DA, which is correlative with the brain function, should be urgently explored. By controlling rigorous anaerobic experimental conditions, this work investigated the molecular mechanism of the Aβ/DA interaction, and two binding sites were revealed. For the binding of DA, Tyrosine (Tyr10) was identified as the strong binding site, and serine-asparagine-lysing (SNK(26-28)) segment was the weak binding segment. Furthermore, the Thioflavin T (THT) fluorescence confirmed DA's positive function of inhibiting Aβ aggregation through its weakly binding with SNK(26-28) segment. Meanwhile, 7-OHCCA fluorescence exhibited DA'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 DA, Cu2+, and Aβ induced lower cell viability than free Cu2+, indicating the significant negative effect of excessive DA on AD progression. This research revealed the potential DA-induced damage in AD brain, which is significant for understanding the function of DA in AD neuropathology and for designing a DA-related therapeutic strategy for AD.
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China.
Mengmeng
M
Liu
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China.
Lu
L
Kou
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China.
Yannan
Y
Bin
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China.
Liping
L
Wan
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China. Electronic address: xiangj@csu.edu.cn.
Juan
J
Xiang
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000633:toxicity*; D004298:Dopamine / Q000633:toxicity*; D006801:Humans; D010446:Peptide Fragments / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003300:Copper; D004298:Dopamine
Amyloid β peptide; Binding; Cytotoxicity; Dopamine; Fibril