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首页> 外文期刊>Journal of Alzheimer's disease: JAD >4-O-methylhonokiol attenuated memory impairment through modulation of oxidative damage of enzymes involving amyloid-beta generation and accumulation in a mouse model of Alzheimer's disease.
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4-O-methylhonokiol attenuated memory impairment through modulation of oxidative damage of enzymes involving amyloid-beta generation and accumulation in a mouse model of Alzheimer's disease.

机译：4-O-甲基厚朴酚通过调节涉及阿尔茨海默氏病小鼠模型中涉及淀粉样β生成和积累的酶的氧化损伤来减轻记忆障碍。

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摘要

Accumulations of amyloid-beta (Abeta) and oxidative damage are critical pathological mechanisms in the development of Alzheimer's disease (AD). We previously found that 4-O-methylhonokiol, a compound extracted from Magnolia officinalis, improved memory dysfunction in Abeta-injected and presenilin 2 mutant mice through the reduction of accumulated Abeta. To investigate mechanisms of the reduced Abeta accumulation, we examined generation, degradation, efflux and aggregation of Abeta in Swedish AbetaPP AD model (AbetaPPsw) mice pre-treated with 4-O-methylhonokiol (1.0 mg/kg) for 3 months. 4-O-methylhonokiol treatment recovered memory impairment and prevented neuronal cell death. This memory improving activity was associated with 4-O-methylhonokiol-induced reduction of Abeta1-42 accumulation in the brains of AbetaPPsw mice. According to the reduction of Abeta1-42 accumulation, 4-O-methylhonkiol modulated oxidative damage sensitive enzymes. 4-O-methylhonkiol decreased expression and activity of brain beta-site AbetaPP cleaving enzyme (BACE1), but increased clearance of Abeta in the brain through an increase of expressions and activities of Abeta degradation enzymes; insulin degrading enzyme and neprilysin. 4-O-methylhonkiol also increased expression of Abeta transport molecule, low density lipoprotein receptor-related protein-1 in the brain and liver. 4-O-methylhonkiol decreased carbonyl protein and lipid peroxidation, but increased glutathione levels in the brains of AbetaPPsw mice suggesting that oxidative damage of protein and lipid is critical in the impairment of those enzyme activities. 4-O-methylhonokiol treatment also prevented neuronal cell death in the AbetaPPsw mousee brain through inactivation of caspase-3 and BAX. These results suggest that 4-O-methylhonokiol might prevent the development and progression of AD by reducing Abeta accumulation through an increase of clearance and decrease of Abeta generation via antioxidant mechanisms.
机译：淀粉样β（Abeta）的积累和氧化损伤是阿尔茨海默病（AD）发生的关键病理机制。我们以前发现4-O-methylhonokiol，从木兰提取的化合物，通过减少累积的Abeta改善了注射Abeta和早老素2突变小鼠的记忆功能障碍。为了研究减少Abeta积累的机制，我们检查了在用4-O-甲基厚朴酚（1.0 mg / kg）预处理3个月的瑞典AbetaPP AD模型（AbetaPPsw）小鼠中Abeta的产生，降解，外排和聚集。 4-O-甲基厚朴酚治疗可恢复记忆障碍并预防神经元细胞死亡。这种记忆改善活动与4-O-甲基厚朴酚诱导的AbetaPPsw小鼠大脑中Abeta1-42积累的减少有关。根据减少的Abeta1-42积累，4-O-甲基苯酚调节氧化损伤敏感性酶。 4-O-methylhonkiol降低了大脑β位AbetaPP裂解酶（BACE1）的表达和活性，但通过增加Abeta降解酶的表达和活性来增加了大脑中Abeta的清除率;胰岛素降解酶和脑啡肽酶。 4-O-甲基苯酚还增加了脑和肝脏中Abeta转运分子，低密度脂蛋白受体相关蛋白1的表达。 4-O-甲基苯酚降低了AbetaPPsw小鼠大脑中的羰基蛋白和脂质过氧化作用，但增加了谷胱甘肽水平，这表明蛋白质和脂质的氧化损伤对这些酶活性的损害至关重要。 4-O-甲基厚朴酚处理还通过使caspase-3和BAX失活来预防AbetaPPsw小鼠大脑中的神经元细胞死亡。这些结果表明4-O-甲基厚朴酚可能通过清除率的增加和通过抗氧化剂机制减少Abeta的产生而减少Abeta的积累，从而阻止AD的发展和进程。

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