Complicated function of dopamine in A?-related neurotoxicity: Dual interactions with Tyr10 and SNK(26

By Liu, Mengmeng; Kou, Lu; Bin, Yannan; Wan, Liping; Xiang, Juan
Published in Journal of Inorganic Biochemistry NULL 2016

Abstract

Abstract With the capability to inhibit the formation of amyloid ? peptides (A?) 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 A? 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 A?. The molecular mechanism by which A? 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 A?/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 A? 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 A?/Cu2 + coordination. The viability tests of the neuroblastoma SH-SY5Y cells displayed that the coexistence of DA, Cu2 +, and A? 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.

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