title: Inhibitory act of selenoprotein P on Cu(+)/Cu(2+)-induced tau aggregation and neurotoxicity.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by peptide and protein misfolding and aggregation, in part due to the presence of excess metal ions such as copper. Aggregation and cytotoxicity of amyloid-β (Aβ) peptide with copper ion have been investigated extensively; however, the effects of metalation on tau are less known. Here, we presented the effects of Cu(+) and Cu(2+) on aggregation and neurotoxicity of the second repeat unit of the microtubule-binding domain of tau (tau-R2). Tau-R2 was demonstrated to bind 0.44 Cu(2+) and 0.34 Cu(+) per monomer with dissociation constants of 1.1 nM and 0.2 pM, respectively. Copper in both oxidation states stimulated the aggregation, ROS production, and neuronal cytotoxicity of tau-R2. We showed that copper-associated tau-R2 aggregates, decreased protein levels of microtubule-associated protein 2 (MAP-2), and synaptophysin in the primarily cultured cortical neurons, reduced mitochondrial density and mobility in the axon and, as a consequence, impaired the growth and probably also the function of neurons. Previously, we reported that the His-rich domain of selenoprotein P (SelP-H) inhibited metal-induced aggregation and toxicity of Aβ, due to its metal chelation ability. Here we demonstrated that SelP-H not only inhibited copper-mediated tau aggregation but also interfered with the ongoing aggregation and reversed the already formed aggregates. More intriguing, SelP-H significantly attenuated Cu(2+)/Cu(+)-tau-R2-induced intracellular ROS production and the impairments of synapse and mitochondrial movement in neurons. This work implies that the surface-exposed His-rich domain of SelP makes it capable of modulating Cu(+)/Cu(2+)-mediated aggregation and neurotoxicity of both Aß and tau and may play important roles in the prevention of AD progression.
authors.affiliation: Department of Marine Biology, Shenzhen Key Laboratory of Marine Biotechnology and Ecology and ‡College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University , Shenzhen 518060, China.
authors.forename: Xiubo
authors.initials: X
authors.lastname: Du
authors.forename: Youbiao
authors.initials: Y
authors.lastname: Zheng
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.forename: Yijing
authors.initials: Y
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Guoli
authors.initials: G
authors.lastname: Song
authors.forename: Jiazuan
authors.initials: J
authors.lastname: Ni
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051149:Selenoprotein P / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D051149:Selenoprotein P; D016875:tau Proteins; D003300:Copper