Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice
Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice
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DOI：
10.1007/s12035-016-9795-4
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发表时间：
2017-04-01
影响因子：
5.1
通讯作者：
Kim, Myeong Ok
中科院分区：
文献类型：
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作者：
Ahmad, Ashfaq;Ali, Tahir;Kim, Myeong Ok
阿尔茨海默病（AD）是一种破坏性和进行性神经退行性疾病，其病理特征在于脑中淀粉样蛋白β（A β）的积累和tau蛋白的过度磷酸化。A β聚集体的沉积触发突触功能障碍、tau的过度磷酸化和神经变性，这导致认知障碍。在这里，我们研究了非瑟酮在A β（1-42）AD小鼠模型中的神经保护作用。单次脑室内注射A β（1-42）（3 μ l/5 min/小鼠）可显著诱导记忆/突触缺陷、神经炎症和神经变性。在A β（1-42）注射后24小时开始以20 mg/kg/天的剂量腹膜内注射非瑟酮2周，可显著降低A β（1-42）诱导的A β蓄积、BACE-1表达和tau蛋白丝氨酸413的过度磷酸化。非瑟酮治疗还通过增加突触前（SYN和SNAP-25）和突触后蛋白（PSD-95、SNAP-23、p-GluR 1（Ser 845）、p-CREB（Ser 133）和p-CAMK II（Thr 286））的水平显著逆转A β（1-42）诱导的突触功能障碍，并最终改善小鼠记忆，如Morris水迷宫试验中所观察到的。在A β（1-42）处理的小鼠中，非瑟酮显著激活p-PI 3 K、p-Akt（Ser 473）和p-GSK 3 β（Ser 9）表达。此外，非瑟酮通过抑制各种激活的神经炎症介质和神经胶质增生来预防神经炎症;它还抑制了小鼠海马中A β（1-42）注射引发的凋亡性神经变性。Fluorojade-B和caspase-3的免疫组织化学染色显示，非瑟酮可防止A β（1-42）治疗小鼠的神经变性。我们的研究结果表明，非瑟酮对A β（1-42）诱导的神经毒性具有有效的神经保护作用。这些结果表明，多酚类黄酮如非瑟酮可能是一种有益的，有效的和安全的神经保护剂，用于预防神经系统疾病，如AD。
Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease and is characterized pathologically by the accumulation of amyloid beta (A beta) and the hyperphosphorylation of tau proteins in the brain. The deposition of A beta aggregates triggers synaptic dysfunction, hyperphosphorylation of tau, and neurodegeneration, which lead to cognitive disorders. Here, we investigated the neuroprotective effect of fisetin in the A beta(1-42) mouse model of AD. Single intracerebroventricular injections of A beta(1-42) (3 mu l/5 min/mouse) markedly induced memory/synaptic deficits, neuroinflammation, and neurodegeneration. Intraperitoneal injections of fisetin at a dose of 20 mg/kg/day for 2 weeks starting 24 h after A beta(1-42) injection significantly decreased the A beta(1-42)-induced accumulation of A beta, BACE-1 expression, and hyperphosphorylation of tau protein at serine 413. Fisetin treatment also markedly reversed A beta(1-42)-induced synaptic dysfunction by increasing the levels of both presynaptic (SYN and SNAP-25) and postsynaptic proteins (PSD-95, SNAP-23, p-GluR1 (Ser 845), p-CREB (Ser 133) and p-CAMKII (Thr 286) and ultimately improved mouse memory, as observed in the Morris water maze test. Fisetin significantly activated p-PI3K, p-Akt (Ser 473), and p-GSK3 beta (Ser 9) expression in A beta(1-42)-treated mice. Moreover, fisetin prevented neuroinflammation by suppressing various activated neuroinflammatory mediators and gliosis; it also suppressed the apoptotic neurodegeneration triggered by A beta(1-42) injections in the mouse hippocampus. Fluorojade-B and immunohistochemical staining for caspase-3 revealed that fisetin prevented neurodegeneration in A beta(1-42)-treated mice. Our results suggest that fisetin has a potent neuroprotective effect against A beta(1-42)-induced neurotoxicity. These results demonstrate that polyphenolic flavonoids such as fisetin could be a beneficial, effective and safe neuroprotective agent for preventing neurological disorders such as AD.