Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC., 3052, Australia.
Neurotoxicology. 2019 May;72:1-5. doi: 10.1016/j.neuro.2019.01.005. Epub 2019 Jan 18.
The accumulation of amyloid-β (Aβ), a constituively-generated peptide, in the brain is considered an upstream event in pathogenesis of Alzheimer's disease. Aβ-induced pathophysiology has been extensively studied in experimental mice and rats. However, neurotoxicity of murine Aβ is much less understood than human Aβ. Here we report difference in ability for extracellular Zn influx into dentate granule cells of rats between human and rat Aβ and its significance. Human Aβ rapidly increased intracellular Zn, which was determined with intracellular ZnAF-2, in dentate granule cells, 5 min after injection of Aβ (25 μM, 1 μl) into the dentate gyrus, while rat Aβ did not increase intracellular Zn. In vivo perforant pathway LTP was attenuated under pre-perfusion with 5 nM human Aβ in artificial cerebrospinal fluid (ACSF) containing 10 nM Zn, recapitulating the concentration of extracellular Zn, but not with 5 nM rat Aβ in ACSF containing 10 nM Zn. The present study suggests that rat Aβ has lower affinity for extracellular Zn than human Aβ and does not capture Zn in the extracellular compartment, resulting in no significant effect on cognitive activity of rat even in the range of very low nanomolar concentrations of endogenous Aβ.
淀粉样蛋白-β（Aβ）的积累被认为是阿尔茨海默病发病机制的上游事件，Aβ 诱导的病理生理学在实验小鼠和大鼠中得到了广泛研究。然而，与人类 Aβ 相比，鼠 Aβ 的神经毒性了解得较少。在这里，我们报告了人和鼠 Aβ 之间细胞外 Zn 流入大鼠齿状回颗粒细胞的能力差异及其意义。在将 Aβ（25μM，1μl）注射到齿状回后 5 分钟，用细胞内 ZnAF-2 测定，人 Aβ 迅速增加了齿状回颗粒细胞内的细胞内 Zn，而鼠 Aβ 则没有增加细胞内 Zn。在含有 10nM Zn 的人工脑脊液（ACSF）中，用 5nM 人 Aβ 预先灌注会减弱活体穿通通路长时程增强（LTP），这与细胞外 Zn 的浓度相吻合，但用含有 10nM Zn 的 ACSF 中的 5nM 鼠 Aβ 则不会减弱。本研究表明，与人类 Aβ 相比，鼠 Aβ 对细胞外 Zn 的亲和力较低，并且不会在细胞外间隙捕获 Zn，因此即使在非常低的纳米摩尔浓度的内源性 Aβ 范围内，也不会对大鼠的认知活动产生显著影响。
