Xu Wei, Xu Qiming, Cheng Hao, Tan Xiangshi
Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
College of Biological & Chemical Sciences and Engineering, Jiaxing University, Jiaxing, 314001, China.
Sci Rep. 2017 Oct 23;7(1):13763. doi: 10.1038/s41598-017-12800-x.
Alzheimer's disease (AD) is one of the leading causes of death for people over 65 years. Worse still, no completely effective therapeutic agent is available so far. One important pathological hallmark of AD is accumulated amyloid-β (Aβ) plaques with dysregulated metal homeostasis. Human metallothionin 3 (MT3), a regulator of metal homeostasis, is downregulated at least 30% in AD brain. So far, some in vitro studies demonstrated its multiple functions related to AD. However, it is a great pity that systematic in vivo studies of MT3 on AD model animals are still a blank so far. In this study, we treated APP/PS1 mice with sustained drug release of ZnMT3 directly to the central nervous system, and investigated the role and molecular mechanism of ZnMT3 to protect against AD mice systematically. The results demonstrated that ZnMT3 can significantly ameliorate cognitive deficits, regulate metal homeostasis, abolish Aβ plaque load, and reduce oxidative stress. Additionally, it has been confirmed that MT3 is penetrable to the blood brain barrier of AD mice. All these results support that ZnMT3 is an effective AD suppressing agent and has potential for applications in Alzheimer's disease therapy.
阿尔茨海默病（AD）是65岁以上人群的主要死因之一。更糟糕的是，迄今为止尚无完全有效的治疗药物。AD的一个重要病理标志是淀粉样β蛋白（Aβ）斑块堆积且金属稳态失调。人类金属硫蛋白3（MT3）作为金属稳态的调节因子，在AD大脑中下调至少30%。到目前为止，一些体外研究证明了其与AD相关的多种功能。然而，遗憾的是，迄今为止关于MT3在AD模型动物上的系统性体内研究仍是空白。在本研究中，我们将ZnMT3持续药物释放直接作用于APP/PS1小鼠的中枢神经系统，系统地研究了ZnMT3对AD小鼠的保护作用及其分子机制。结果表明，ZnMT3可显著改善认知缺陷、调节金属稳态、消除Aβ斑块负荷并减轻氧化应激。此外，已证实MT3可穿透AD小鼠的血脑屏障。所有这些结果都支持ZnMT3是一种有效的AD抑制药物，在阿尔茨海默病治疗中具有应用潜力。
