Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARγ dependent signaling
Rosiglitazone rescues human neural stem cells from amyloid-beta induced ER stress via PPARγ dependent signaling
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DOI：
10.1016/j.yexcr.2018.06.033
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发表时间：
2018-09-15
影响因子：
3.7
通讯作者：
Chiang, Ming-Chang
中科院分区：
文献类型：
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作者：
Lin, Chien-Hung;Nicol, Christopher J. B.;Chiang, Ming-Chang
过氧化物酶体增殖体激活受体γ (PPAR γ)属于一个已知的配体激活的核受体家族，调节许多重要的生理和病理条件。事实上，PPAR γ转录活性的改变有助于代谢综合征（与2型糖尿病相关的肥胖和高血糖）、中风和神经退行性疾病。各种研究表明PPAR γ激动剂影响阿尔茨海默病（AD）患者和AD啮齿动物模型的神经元缺陷。淀粉样蛋白- (AD)是一种与AD神经元损伤发病机制相关的神经病理标志物，其表达与PPAR γ依赖性神经保护反应的激活呈负相关。然而，PPAR γ激动剂在AD中的作用的分子机制仍有待阐明。在这里，我们探索了PPAR γ信号通路和网络，这些通路和网络可以防止A β诱导的内质网（ER）应激（如caspase 4、Bip、CHOP、ASK1和ER钙）、细胞死亡（如活力和细胞色素c）和线粒体缺陷（如最大呼吸功能、COX活性和线粒体膜电位）事件。与GW9662 （PPAR γ拮抗剂）联合治疗有效地阻断了罗格列酮的这些保护作用，提供了强有力的证据，证明PPAR γ依赖性信号可以拯救hNSCs免受A β介导的毒性。总之，我们的数据表明，PPAR γ通路的激活可能对预防ad相关的内质网应激、内质网失衡和线粒体缺陷至关重要。这些发现也提高了我们对PPAR γ在hNSCs中的作用的理解，并可能有助于开发和实施治疗AD的新治疗策略。
Peroxisome proliferator-activated receptor gamma (PPAR gamma) belongs to a family of ligand-activated nuclear receptors known to regulate many crucial physiological and pathological conditions. Indeed, altered PPAR gamma transcriptional activity contributes to metabolic syndromes (obesity and hyperglycemia associated with type 2 diabetes mellitus), stroke and neurodegenerative diseases. various studies suggest that PPAR gamma agonists influence neuronal deficits in Alzheimer's Disease (AD) patients and rodent models of AD. Expression of amyloid-beta (AD), a neuropathological marker associated with the pathogenesis of AD neuronal impairment, is inversely correlated with the activation of PPAR gamma-dependent neuroprotective responses. Nevertheless, molecular mechanisms by which the effects of PPAR gamma agonists in AD remain to be clarified. Here, we explore the PPAR gamma signaling pathways and networks that protect against A beta-induced endoplasmic reticulum (ER) stress (e.g., caspase 4, Bip, CHOP, ASK1 and ER calcium), cell death (e.g., viability and cytochrome c) and mitochondrial deficiency (e.g., maximal respiratory function, COX activity, and mitochondrial membrane potential) events in the human neural stem cells (hNSCs) treated with A beta. Co-treatment with GW9662 (an antagonist of PPAR gamma) effectively blocked these protective effects by rosiglitazone, providing strong evidence that PPAR gamma-dependent signaling rescues hNSCs from A beta-mediated toxicity. Together, our data suggest activation of PPAR gamma pathway might be critical to protecting against AD-related ER stress, ER disequilibrium and mitochondrial deficiency. These findings also improve our understanding of the role of PPAR gamma in hNSCs, and may aid in the development and implementation of new therapeutic strategies for the treatment of AD.