Chiang Ming-Chang, Nicol Christopher J B, Cheng Yi-Chuan, Yen Chiahui, Lin Chien-Hung, Chen Shiang-Jiuun, Huang Rong-Nan
Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Departments of Pathology & Molecular Medicine and Biomedical & Molecular Sciences, and Cancer Biology and Genetics Division, Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
Neuroscience. 2020 May 21;435:44-57. doi: 10.1016/j.neuroscience.2020.03.040. Epub 2020 Mar 27.
Alzheimer's disease (AD) is a neuronal dementia with progressive memory loss. Amyloid-beta (Aβ) peptides has major effect in the neurodegenerative disorder, which are thought to promote mitochondrial dysfunction in AD brains. Anti-AD drugs acting upon the brain are generally difficult to develop, often cause serious side effects or lack therapeutic efficacy. Numerous studies have shown the beneficial therapeutic applications of gold nanoparticles (AuNPs), including for neuroprotective events and AD. The aim of this study is to understand how AuNPs could exert their neuroprotective role in AD, for which cell model have chosen human neural stem cells (hNSCs) as the experimental tool. We hypothesize AuNPs protect against Aβ-induced cellular impairment and mitochondrial dysfunction in hNSCs. Here, we show AuNPs increase the survival of hNSCs treated with Aβ via downregulation of caspase 3 and 9 activities. Moreover, AuNPs abrogated the Aβ-mediated decrease neuroprotective (CREB and Bcl-2) and mitochondrial (PGC1α, NRF-1 and Tfam) gene expressions in treated hNSCs. Importantly, co-treatment with AuNPs significantly rescued hNSCs from Aβ-mediated mitochondrial function and morphology. AuNPs also significantly normalizes the immunostaining of mitochondrial marker and mass in differentiated hNSCs with Aβ. The effects may be exerted by the AuNPs, as supported by its protective reversal of Aβ-induced cellular impairment and mitochondrial dysfunction in hNSCs. In fact, the results presented extend our understanding of the mechanisms through which AuNPs could exert their neuroprotective role in hNSCs treated with Aβ.
阿尔茨海默病（AD）是一种伴有进行性记忆丧失的神经元性痴呆。β-淀粉样蛋白（Aβ）肽在这种神经退行性疾病中具有主要作用，被认为会促进AD大脑中的线粒体功能障碍。作用于大脑的抗AD药物通常难以研发，常常会引起严重的副作用或缺乏治疗效果。大量研究表明了金纳米颗粒（AuNPs）的有益治疗应用，包括对神经保护作用和AD的应用。本研究的目的是了解AuNPs如何在AD中发挥其神经保护作用，为此选择了人类神经干细胞（hNSCs）作为细胞模型进行实验。我们假设AuNPs可保护hNSCs免受Aβ诱导的细胞损伤和线粒体功能障碍。在此，我们表明AuNPs通过下调半胱天冬酶3和9的活性来提高经Aβ处理的hNSCs的存活率。此外，AuNPs消除了Aβ介导的经处理的hNSCs中神经保护基因（CREB和Bcl-2）以及线粒体基因（PGC1α、NRF-1和Tfam）表达的降低。重要的是，与AuNPs共同处理可显著挽救hNSCs免受Aβ介导的线粒体功能和形态损伤。AuNPs还显著使经Aβ处理的分化hNSCs中线粒体标志物的免疫染色和质量正常化。AuNPs可能发挥了这些作用，这得到了其对Aβ诱导的hNSCs细胞损伤和线粒体功能障碍的保护性逆转的支持。事实上，所呈现的结果扩展了我们对AuNPs在经Aβ处理的hNSCs中发挥神经保护作用机制的理解。
