Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer's disease-like pathologies.
Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer's disease-like pathologies.
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DOI：
10.1038/s41598-017-12632-9
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发表时间：
2017-09-29
影响因子：
4.6
通讯作者：
Kim MO
中科院分区：
文献类型：
--
作者：
Kim MW;Abid NB;Jo MH;Jo MG;Yoon GH;Kim MO
近年来对神经退行性变的研究主要集中在中枢神经系统能量代谢功能障碍和蛋白质病变。脂联素（Adiponectin，ADPN）是一种脂肪细胞源性激素，通过脂联素受体调节外周器官的胰岛素敏感性和葡萄糖稳态。尽管越来越多的证据表明脂联素具有神经保护作用，但脂联素受体的潜在作用尚未阐明。在这里，使用基因治疗介导的抑制与shRNA，我们发现，脂联素受体1（AdipoR 1）抑制诱导神经退行性变以及代谢功能障碍。AdipoR 1基因敲除小鼠表现出体重增加和血浆化学异常，在行为研究中也表现出空间学习和记忆障碍。此外，AdipoR 1抑制导致神经退行性表型，减少神经元标记物NeuN的表达，并增加caspase 3的表达和活性。此外，在AdipoR 1敲除组中高度显示AD样病理学，包括胰岛素信号传导功能障碍、异常蛋白聚集和神经炎症反应，这与ADPN敲除小鼠的脑病理学一致。总之，这些结果表明ADPN-AdipoR 1信号传导具有减轻神经退行性疾病如阿尔茨海默病的潜力。
Recent studies on neurodegeneration have focused on dysfunction of CNS energy metabolism as well as proteinopathies. Adiponectin (ADPN), an adipocyte-derived hormone, plays a major role in the regulation of insulin sensitivity and glucose homeostasis in peripheral organs via adiponectin receptors. In spite of accumulating evidence that adiponectin has neuroprotective properties, the underlying role of adiponectin receptors has not been illuminated. Here, using gene therapy-mediated suppression with shRNA, we found that adiponectin receptor 1 (AdipoR1) suppression induces neurodegeneration as well as metabolic dysfunction. AdipoR1 knockdown mice exhibited increased body weight and abnormal plasma chemistry and also showed spatial learning and memory impairment in behavioural studies. Moreover, AdipoR1 suppression resulted in neurodegenerative phenotypes, diminished expression of the neuronal marker NeuN, and increased expression and activity of caspase 3. Furthermore, AD-like pathologies including insulin signalling dysfunction, abnormal protein aggregation and neuroinflammatory responses were highly exhibited in AdipoR1 knockdown groups, consistent with brain pathologies in ADPN knockout mice. Together, these results suggest that ADPN-AdipoR1 signalling has the potential to alleviate neurodegenerative diseases such as Alzheimer’s diseases.
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