Extracellular Zn2+-Dependent Amyloid-β1-42 Neurotoxicity in Alzheimer's Disease Pathogenesis
Extracellular Zn2+-Dependent Amyloid-β1-42 Neurotoxicity in Alzheimer's Disease Pathogenesis
复制标题
阿尔茨海默病发病机制中细胞外 Zn2+ 依赖性淀粉样蛋白-β1-42 的神经毒性
DOI：
10.1007/s12011-020-02131-w
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Takeda A
中科院分区：
文献类型：
--
作者：
Sato Y;Takiguchi M;Tamano H;Takeda A
海马细胞外Zn2+的基础水平在低纳摩尔（~ 10 nM）范围内。然而，细胞外Zn2+动力学不仅在认知活动中起关键作用，而且在认知衰退中也起关键作用。胞外Zn2+动力学可通过谷氨酸能突触兴奋和淀粉样蛋白-β1-42 （a -β1-42）的存在而改变，淀粉样蛋白-β1-42是阿尔茨海默病（AD）的致病肽。当人a - β1 - 42在大鼠齿状回细胞外区达到高皮摩尔（bbb100 pM）时，锌- a - β1 - 42复合物容易形成并被齿状颗粒细胞吸收，随后a - β1 - 42诱导认知能力下降，这与细胞内zn - a - β1 - 42复合物释放的Zn2+有关。a - β1 - 42诱导的细胞内Zn2+毒性随着年龄的增长而加速，因为细胞外Zn2+随着年龄的增长而增加。最近的研究结果表明，神经元末梢持续分泌的a β1 - 42通过细胞内Zn2+的失调导致与年龄相关的认知能力下降和神经退行性变。另一方面，金属硫蛋白（MTs），锌结合蛋白，在急性细胞内Zn2+失调时迅速为细胞内Zn2+提供缓冲。基于对a β1 - 42诱导的发病机制的防御策略可以阻止AD的发展，本文综述了细胞外Zn2+依赖性a β1 - 42神经毒性，这种神经毒性随着年龄的增长而加速。
The basal level of extracellular Zn2+is in the range of low nanomolar (~ 10 nM) in the hippocampus. However, extracellular Zn2+dynamics plays a key role for not only cognitive activity but also cognitive decline. Extracellular Zn2+dynamics is modified by glutamatergic synapse excitation and the presence of amyloid-β1–42(Aβ1–42), a causative peptide in Alzheimer’s disease (AD). When human Aβ1–42reaches high picomolar (> 100 pM) in the extracellular compartment of the rat dentate gyrus, Zn-Aβ1–42complexes are readily formed and taken up into dentate granule cells, followed by Aβ1–42-induced cognitive decline that is linked with Zn2+released from intracellular Zn-Aβ1–42complexes. Aβ1–42-induced intracellular Zn2+toxicity is accelerated with aging because of age-related increase in extracellular Zn2+. The recent findings suggest that Aβ1–42secreted continuously from neuron terminals causes age-related cognitive decline and neurodegeneration via intracellular Zn2+dysregulation. On the other hand, metallothioneins (MTs), zinc-binding proteins, quickly serve for intracellular Zn2+-buffering under acute intracellular Zn2+dysregulation. On the basis of the idea that the defense strategy against Aβ1–42-induced pathogenesis leads to preventing the AD development, this review deals with extracellular Zn2+-dependent Aβ1–42neurotoxicity, which is accelerated with aging.