His-Rich Domain of Selenoprotein P Ameliorates Neuropathology and Cognitive Deficits by Regulating TrkB Pathway and Zinc Homeostasis in an Alzheimer Model of Mice,ACS Chemical Neuroscience

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His-Rich Domain of Selenoprotein P Ameliorates Neuropathology and Cognitive Deficits by Regulating TrkB Pathway and Zinc Homeostasis in an Alzheimer Model of Mice
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-11-23 , DOI: 10.1021/acschemneuro.0c00278
Caiping Yue ₁ , Zhifu Shan _{1,

2} , Yibin Tan ₁ , Chuangyu Yao ₁ , Yuanheng Liu ₃ , Qiong Liu _{1,

4} , Xiangshi Tan ₅ , Xiubo Du _{1,

4}

Affiliation

Selenoproteins are a family of special proteins that contain the 21st amino acid, selenocysteine (Sec), in their sequence. Selenoprotein P has 10 Sec residues and modulates selenium homeostasis and redox balance in the brain. Previously, we found that the Sec-devoid His-rich motif of selenoprotein P (Selenop-H) suppressed metal-induced aggregation and neurotoxicities of both Aβ and tau in vitro. To investigate the intervening capacity of Selenop-H on the neuropathology and cognitive deficits of triple transgenic AD (3 × Tg-AD) mice, the Selenop-H gene packaged in rAAV9 was delivered into the hippocampal CA3 regions of mice via stereotaxic injection. Four months later, we demonstrated that Selenop-H (1) improved the spatial learning and memory deficits, (2) alleviated neuron damage and synaptic protein loss, (3) inhibited both tau pathology and amyloid beta protein (Aβ) aggregation, (4) activated both BDNF- and Src-mediated TrkB signaling, and (5) increased MT3 and ZnT3 levels and restored Zn²⁺ homeostasis in the mice model of AD. The study revealed that Selenop-H is potent in ameliorating AD-related neuropathology and cognitive deficits by modulating TrkB signaling and Zn²⁺ homeostasis.

中文翻译：

富含组氨酸的硒蛋白 P 结构域通过调节阿尔茨海默氏症小鼠模型中的 TrkB 通路和锌稳态来改善神经病理学和认知缺陷

硒蛋白是一个特殊的蛋白质家族，其序列中含有第 21 个氨基酸，硒代半胱氨酸 (Sec)。硒蛋白 P 具有 10 秒残基，可调节大脑中的硒稳态和氧化还原平衡。以前，我们发现硒蛋白 P (Selenop-H) 的富含 Sec 的基序在体外抑制了金属诱导的 Aβ 和 tau 的聚集和神经毒性。为了研究 Selenop-H 对三重转基因 AD (3 × Tg-AD) 小鼠神经病理学和认知缺陷的干预能力，将包装在 rAAV9 中的 Selenop-H 基因通过立体定向注射。四个月后，我们证明了 Selenop-H (1) 改善了空间学习和记忆缺陷，(2) 减轻了神经元损伤和突触蛋白丢失，(3) 抑制了 tau 病理学和淀粉样β蛋白 (Aβ) 聚集，(4 ) 激活 BDNF 和 Src 介导的 TrkB 信号传导，以及 (5) 增加 MT3 和 ZnT3 水平并恢复 AD 小鼠模型中的 Zn ²⁺稳态。研究表明，Selenop-H 通过调节 TrkB 信号传导和 Zn ²⁺稳态有效改善 AD 相关的神经病理学和认知缺陷。

更新日期：2020-12-16

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