Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTg-AD mice
Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTg-AD mice
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DOI：
10.1007/s00011-017-1022-x
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发表时间：
2017-05-01
影响因子：
6.7
通讯作者：
Altavilla, Domenica
中科院分区：
文献类型：
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作者：
Bitto, Alessandra;Giuliani, Daniela;Altavilla, Domenica
目的与设计阿尔茨海默病（Alzheimer's disease，AD）与脑内淀粉样斑块（amyloid plaques，A beta）和过度磷酸化的tau蛋白缠结有关。本研究采用3个月龄的三转基因（3xTg-AD）小鼠，研究了黄酮环氧化酶（flavocoxid）（一种环氧化酶1/2（考克斯-1/2）和5-脂氧合酶（5-LOX）的双重抑制剂）对小鼠神经元的保护作用。进行组织学检查以证明A β斑块和神经元丢失，同时通过蛋白质印迹分析确定炎症蛋白。结果盐水处理的3xTg-AD小鼠表现出空间学习和记忆障碍（在6个月大时评估），并且炎症和细胞凋亡分子的表达增加。用黄酮类化合物治疗3xTg-AD小鼠减少：（1）学习和记忆丧失;（2）增加类花生酸的产生和淀粉样前体蛋白的磷酸化水平（APP-pThr 668）、A β 1-42、p-tau（pThr 181）、pERK和NLRP 3炎性体的活化;结论考克斯-1/2和5-LOX的药物阻断能够通过靶向A β和tau蛋白的上下游病理生理机制来对抗AD的进展。
Objective and design Alzheimer's disease (AD) is associated with amyloid plaques (A beta) and hyperphosphorylated tau protein tangles in the brain. We investigated the possible neuroprotective role of flavocoxid, a dual inhibitor of cyclooxygenases-1/2 (COX-1/2) and 5-Lipoxygenase (5-LOX), in triple-transgenic (3xTg-AD) mice.Subjects Mice were 3 months at the beginning of the study.Treatment Animals received once daily for 3-month saline solution or flavocoxid (20 mg/kg/ip).Methods Morris water maze was used to assess learning and memory. Histology was performed to evidence A beta plaques and neuronal loss, while inflammatory proteins were determined by western blot analysis.Results Saline-treated 3xTg-AD mice showed an impairment in spatial learning and memory (assessed at 6 months of age), and increased expression of inflammatory and apoptotic molecules. Treatment of 3xTg-AD mice with flavocoxid reduced: (1) learning and memory loss; (2) the increased eicosanoid production and the phosphorylation level of amyloid precursor protein (APP-pThr668), A beta 1-42, p-tau (pThr181), pERK, and the activation of the NLRP3 inflammasome; (3) A beta plaques; and (4) neuronal loss, compared to saline-treated animals.Conclusions Pharmacological blockade of both COX-1/2 and 5-LOX was able to counteract the progression of AD by targeting pathophysiological mechanisms up- and downstream of A beta and tau.