Xinyao Zhang,Xu Yang,Dongpei Zhuang,Zhiyi Mu,Chuanxia Ju
Neuronal hyperexcitability is crucial to the pathogenesis of Alzheimer's disease (AD). Activating the Kv7 channel is an effective way to reduce neuronal excitability. The Kv7 channel opener retigabine (RTG) has been demonstrated to alleviate spatial memory deficits in APP/PS1 transgenic mice. However, the mechanism by which RTG reduces cognitive deficits in APP/PS1 mice remains unclear. In this study, we revealed that RTG could ameliorate learning and spatial memory deficits in APP/PS1 mice during novel object recognition and Morris water maze tests. Meanwhile, RTG increased NeuN neuronal fluorescence intensity, increased the expression of the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN), improved synaptic plasticity, increased insulin-degrading enzyme (IDE) expression, decreased beta-secretase 1 (BACE1) expression, reduced Aβ 1–40 and Aβ 1–42 levels, and increased pAKT (ser473) and pGSK-3β (ser9) expression. These results indicated that RTG alleviates learning and spatial memory deficits in APP/PS1 mice, with potential mechanisms involving a reduction in neuronal loss, attenuation of synaptic damage, a decrease in β-amyloid (Aβ) deposition, and activation of the AKT/GSK-3β pathway.
Kun Zhang,Jiahui Liang,Nadja R. Brun,Yanbin Zhao,Andreas A. Werdich
Rapid and cost-effective in vivo assays to screen potential environmental neurodevelopmental toxicants are necessary to address the limitations of in vitro platforms, such as the inability to fully recapitulate the developmental and physiological processes of whole organisms. In the present study, a rapid zebrafish behavioral profiling assay was developed to characterize the neurodevelopmental effects of environmental substances by quantitatively evaluating multiple spontaneous movement features of zebrafish embryos. This video analysis-based assay automatically segmented every embryo and thus was able to accurately quantify spontaneous movement features, including frequency, duration, intensity, interval, and the number of continuous movements. When tested with eight environmental substances known to be neurodevelopmental toxicants, such as chlorpyrifos and bisphenol A, the assay successfully captured frequency alterations that were well-documented in previous studies while also providing additional information. Using an optimized procedure, we further assessed 132 potential neurotoxins that spanned a wide range of molecular targets, many of which were previously detected in environmental waterbodies. The distinct altered behavioral barcodes indicated that the spontaneous movement was impacted by diverse neuroactive substances, and the effects could be effectively evaluated with the developed assay. The web-based tool, named EMAnalysis, is further provided at http://www.envh.sjtu.edu.cn/zebrafish_contraction.jsp. Thus, this assay provides an efficient platform to accelerate the pace of neurotoxic environmental contaminant discoveries.
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