Adlard Paul A, Parncutt Jacqui, Lal Varsha, James Simon, Hare Dominic, Doble Philip, Finkelstein David I, Bush Ashley I
The Florey Institute for Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria 3052, Australia.
The Mental Health Research Institute, Parkville, Victoria 3052, Australia.
Neurobiol Dis. 2015 Sep;81:196-202. doi: 10.1016/j.nbd.2014.12.012. Epub 2014 Dec 27.
Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95; AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippocampus. While we demonstrated a small regional increase in hippocampal zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippocampal formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease.
锌转运体3（ZnT3）蛋白负责将锌装载到突触前囊泡中，从而控制谷氨酸能突触处锌的可用性。已表明ZnT3会随着年龄增长以及在阿尔茨海默病（AD）中下降，并且在学习和记忆中起关键作用。在本研究中，我们利用ZnT3基因敲除小鼠品系进行全动物行为分析，并对ZnT3基因敲除小鼠脑片的长时程增强进行电生理分析，以表明金属伴侣分子（氯碘羟喹，30毫克/千克/天，持续6周）可以预防这些动物特有的年龄依赖性认知表型。这可能是由于突触蛋白表达的稳态恢复，因为氯碘羟喹显著恢复了对正常认知至关重要的各种突触前和突触后蛋白的水平，包括PSD-95、AMPA受体和NMDA受体2b。我们推测，氯碘羟喹介导的突触健康恢复是由于海马体中突触锌含量的选择性增加。虽然我们使用同步加速器X射线荧光显微镜证明了海马体锌含量有小区域增加，但需要进一步的亚区域分析来确定在海马结构的其他与本研究中观察到的突触可塑性效应更密切相关的区域是否也能看到这种效应。这些数据支持了我们最近关于使用不同金属伴侣分子（PBT2）预防正常年龄相关认知衰退的报告，并表明金属伴侣分子在预防锌介导的、表征衰老和疾病的认知衰退方面是有效的。
