Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system.
Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system.
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DOI：
10.1074/jbc.ra117.001245
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发表时间：
2018-11-23
期刊：
影响因子：
--
通讯作者：
Park J
中科院分区：
文献类型：
--
作者：
Murphy K;Llewellyn K;Wakser S;Pontasch J;Samanich N;Flemer M;Hensley K;Kim DS;Park J
氧化应激会引发并加剧阿尔茨海默病 (AD) 的神经退行性变。各种抗氧化剂可以减少氧化应激，但由于血脑屏障（BBB）通透性差，这些药物效果甚微。此外，单模式抗氧化剂很容易被整体氧化应激所淹没。激活核因子红细胞 2 (NF-E2) 相关因子 2 (Nrf2) 及其下游抗氧化系统被认为对于减少整体氧化应激非常有效。迄今为止，只有少数 BBB 渗透性药物可激活 Nrf2 依赖性抗氧化系统。在这里，我们发现了一种绕过 BBB 的 Nrf2 激活多糖，可以减轻 AD 发病机制。 Mini-GAGR 是低酰基结冷胶的 0.7 kDa 裂解产物，可提高 Nrf2 依赖性抗氧化酶的水平和活性，减少小鼠皮质神经元氧化应激下的活性氧 (ROS)，并强有力地保护线粒体免受氧化损伤。此外，与已知的 Nrf2 激活剂类似，mini-GAGR 增加了 Nrf2 的核定位和转录活性。从机制上讲，mini-GAGR 增加了 Nrf2 与其抑制剂 Kelch 样 ECH 相关蛋白 1 (Keap1) 的解离，并以蛋白激酶 C (PKC) 和成纤维细胞生长因子受体 (FGFR1) 依赖性方式诱导 Nrf2 磷酸化和核转位。最后，用 100 nmol mini-GAGR 对 3xTg-AD 小鼠进行 20 天的鼻内治疗，增加了海马神经元中核 p-Nrf2 和生长相关蛋白 43 (GAP43) 的水平，减少了 p-tau 和 β-淀粉样蛋白 (Aβ) 肽染色的神经元，并改善了记忆力。本文报道的绕过 BBB 的 Nrf2 激活多糖可能有效减少 AD 中的氧化应激和神经退行性变。
Oxidative stress triggers and exacerbates neurodegeneration in Alzheimer's disease (AD). Various antioxidants reduce oxidative stress, but these agents have little efficacy due to poor blood–brain barrier (BBB) permeability. Additionally, single-modal antioxidants are easily overwhelmed by global oxidative stress. Activating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream antioxidant system are considered very effective for reducing global oxidative stress. Thus far, only a few BBB-permeable agents activate the Nrf2-dependent antioxidant system. Here, we discovered a BBB-bypassing Nrf2-activating polysaccharide that may attenuate AD pathogenesis. Mini-GAGR, a 0.7-kDa cleavage product of low-acyl gellan gum, increased the levels and activities of Nrf2-dependent antioxidant enzymes, decreased reactive oxygen species (ROS) under oxidative stress in mouse cortical neurons, and robustly protected mitochondria from oxidative insults. Moreover, mini-GAGR increased the nuclear localization and transcriptional activity of Nrf2 similarly to known Nrf2 activators. Mechanistically, mini-GAGR increased the dissociation of Nrf2 from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), and induced phosphorylation and nuclear translocation of Nrf2 in a protein kinase C (PKC)- and fibroblast growth factor receptor (FGFR1)-dependent manner. Finally, 20-day intranasal treatment of 3xTg-AD mice with 100 nmol of mini-GAGR increased nuclear p-Nrf2 and growth-associated protein 43 (GAP43) levels in hippocampal neurons, reduced p-tau and β-amyloid (Aβ) peptide–stained neurons, and improved memory. The BBB-bypassing Nrf2-activating polysaccharide reported here may be effective in reducing oxidative stress and neurodegeneration in AD.
影响因子：
1.9
作者：
Christopher K;Makani V;Judy W;Lee E;Chiaia N;Kim DS;Park J
通讯作者：
Park J