R-flurbiprofen improves tau, but not Aβ pathology in a triple transgenic model of Alzheimer's disease
R-flurbiprofen improves tau, but not Aβ pathology in a triple transgenic model of Alzheimer's disease
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DOI：
10.1016/j.brainres.2013.10.025
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发表时间：
2013-12-06
期刊：
影响因子：
2.9
通讯作者：
Dedeoglu, Alpaslan
中科院分区：
文献类型：
--
作者：
Carreras, Isabel;McKee, Ann C.;Dedeoglu, Alpaslan
我们以前曾报道过，慢性布洛芬治疗可以改善3xTg-AD小鼠的认知能力，降低细胞内A β和磷酸化tau水平。伊立替尼是一种非甾体抗炎药（NSAID），其抗炎作用独立于其抗炎作用，作为γ-分泌酶调节剂（GSM）具有抗淀粉样蛋白生成活性，两种活性均具有降低A β病理学的潜力。为了进一步了解NSAID在3xTg-AD小鼠中的作用，我们用R-氟比洛芬（一种NSAID氟比洛芬的对映体，其保持GSM活性但抗炎活性大大降低）治疗3xTg-AD小鼠，并分析其对认知、A β、tau和海马神经化学特征的影响。从5至7个月大的R-氟比洛芬治疗导致在径向臂水迷宫（RAWM）测试中的认知改善，并降低了用AT 8和PHF-1抗体免疫染色的过度磷酸化tau蛋白的水平。未检测到A β水平的显著变化（使用6 E10和NU-1抗体）。使用磁共振波谱（MRS），我们发现R-氟比洛芬治疗降低了3xTg-AD小鼠中升高的谷氨酰胺水平，降至非转基因小鼠中检测到的水平。谷氨酰胺水平与PHF-1免疫染色的过度磷酸化tau蛋白相关。我们还发现，在研究中的所有小鼠中，谷氨酸浓度与学习之间存在负相关。谷氨酰胺和谷氨酸，穿梭于神经元和星形胶质细胞之间以维持突触中谷氨酸稳态的神经化学物质，作为认知功能的MR标记物值得进一步关注。由爱思唯尔公司出版
We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular A beta and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease A beta pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, A beta, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of A beta (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function. Published by Elsevier B.V.