Alzheimer's disease (AD) is a neurodegenerative disorder with progressive memory loss resulting in dementia. Amyloid-beta (Aβ) peptides play a critical role in the pathogenesis of this disease, and are thought to promote inflammation and oxidative stress leading to neurodegeneration in the neocortex and hippocampus of the AD brains. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis, and cell survival in response to inflammation and oxidative stress. However, the neuroprotective mechanisms by which AMPK achieves these beneficial effects in human neural stem cells (hNSCs) exposed to Aβ is still not well understood. Resveratrol is a potent activator of AMPK suggesting it may have therapeutic potential against AD. Therefore, we will test the hypothesis that the AMPK activator resveratrol protects against Aβ mediated neuronal impairment (inflammation and oxidative stress) in hNSCs. Here, Aβ-treated hNSCs had significantly decreased cell viability that correlated with increased TNF-α and IL-1β inflammatory cytokine expression. Co-treatment with resveratrol significantly abrogated the Aβ-mediated effects in hNSCs, and was effectively blocked by the addition of the AMPK-specific antagonist (Compound C). These results suggest the neuroprotective effects of resveratrol are mediated by an AMPK-dependent pathway. In addition, resveratrol rescued the transcript expression levels of inhibitory kappa B kinase (IKK) in Aβ-treated hNSCs. NF-κB is a transcription factor with a key role in the expression of a variety of genes involved in inflammatory responses. Resveratrol prevented the Aβ-mediated increases in NF-κB mRNA and protein levels, and its nuclear translocation in hNSCs. Co-treatment with resveratrol also significantly restored iNOS and COX-2 levels in Aβ-treated hNSCs. Furthermore, hNSCs co-treated with resveratrol were significantly rescued from Aβ-induced oxidative stress, which correlated with reversal of the Aβ-induced mRNA decrease in oxidative defense genes (SOD-1, NRF2, Gpx1, Catalase, GSH and HO-1). Taken together, these novel findings show that activation of AMPK-dependent signaling by resveratrol rescues Aβ-mediated neurotoxicity in hNSCs, and provides evidence supporting a neuroprotective role for AMPK activating drugs in Aβ-related diseases such as AD.

阿尔茨海默氏病（AD）是一种神经退行性疾病，伴有进行性记忆丧失，导致痴呆。淀粉样蛋白（Aβ）肽在这种疾病的发病机理中起关键作用，并被认为可促进炎症和氧化应激，导致AD大脑新皮质和海马神经变性。AMP激活的蛋白激酶（AMPK）是细胞能量稳态和响应炎症和氧化应激的细胞存活的主要调节剂。然而，AMPK通过其在暴露于Aβ的人类神经干细胞（hNSCs）中实现这些有益作用的神经保护机制仍未得到很好的了解。白藜芦醇是AMPK的有效激活剂，表明它可能具有抗AD的治疗潜力。所以，我们将测试AMPK激活剂白藜芦醇可防止hNSCs中Aβ介导的神经元损伤（炎症和氧化应激）的假设。在这里，Aβ处理的hNSCs的细胞活力显着降低，这与TNF-α和IL-1β炎性细胞因子表达的增加有关。与白藜芦醇共同治疗可显着消除hNSC中Aβ介导的作用，并通过添加AMPK特异性拮抗剂（化合物C）有效地阻断。这些结果表明白藜芦醇的神经保护作用是由AMPK依赖性途径介导的。此外，白藜芦醇挽救了Aβ处理的hNSCs中抑制性Kappa B激酶（IKK）的转录表达水平。NF-κB是一种转录因子，在涉及炎症反应的多种基因的表达中起关键作用。白藜芦醇可阻止Aβ介导的hNSCsNF-κBmRNA和蛋白水平的增加及其核易位。与白藜芦醇共同治疗还可以显着恢复Aβ治疗的hNSCs中的iNOS和COX-2水平。此外，与白藜芦醇共同治疗的hNSCs可以从Aβ诱导的氧化应激中明显获救，这与Aβ诱导的氧化防御基因（SOD-1，NRF2，Gpx1，过氧化氢酶，GSH和HO-1）的mRNA降低的逆转有关。 。综上所述，这些新发现表明白藜芦醇对AMPK依赖性信号的激活可以挽救hNSC中Aβ介导的神经毒性，并提供证据支持AMPK活化药物在Aβ相关疾病（如AD）中具有神经保护作用。与白藜芦醇共同治疗还可以显着恢复Aβ治疗的hNSCs中的iNOS和COX-2水平。此外，与白藜芦醇共同治疗的hNSCs可以从Aβ诱导的氧化应激中明显获救，这与Aβ诱导的氧化防御基因（SOD-1，NRF2，Gpx1，过氧化氢酶，GSH和HO-1）的mRNA降低的逆转有关。 。综上所述，这些新发现表明白藜芦醇对AMPK依赖性信号的激活可以挽救hNSC中Aβ介导的神经毒性，并提供证据支持AMPK活化药物在Aβ相关疾病（如AD）中的神经保护作用。与白藜芦醇共同治疗还可以显着恢复Aβ治疗的hNSCs中的iNOS和COX-2水平。此外，与白藜芦醇共同治疗的hNSCs可以从Aβ诱导的氧化应激中明显获救，这与Aβ诱导的氧化防御基因（SOD-1，NRF2，Gpx1，过氧化氢酶，GSH和HO-1）的mRNA降低的逆转有关。 。综上所述，这些新发现表明白藜芦醇对AMPK依赖性信号的激活可以挽救hNSC中Aβ介导的神经毒性，并提供证据支持AMPK活化药物在Aβ相关疾病（如AD）中的神经保护作用。与Aβ诱导的氧化防御基因（SOD-1，NRF2，Gpx1，过氧化氢酶，GSH和HO-1）的mRNA降低相关。综上所述，这些新发现表明白藜芦醇对AMPK依赖性信号的激活可以挽救hNSC中Aβ介导的神经毒性，并提供证据支持AMPK活化药物在Aβ相关疾病（如AD）中的神经保护作用。与Aβ诱导的氧化防御基因（SOD-1，NRF2，Gpx1，过氧化氢酶，GSH和HO-1）的mRNA降低相关。综上所述，这些新发现表明白藜芦醇对AMPK依赖性信号的激活可以挽救hNSC中Aβ介导的神经毒性，并提供证据支持AMPK活化药物在Aβ相关疾病（如AD）中的神经保护作用。