转基因小鼠
γ分泌酶
海马体
淀粉样前体蛋白
淀粉样前体蛋白分泌酶
细胞内
转基因
化学
淀粉样蛋白(真菌学)
分子生物学
药理学
内科学
内分泌学
阿尔茨海默病
生物
医学
生物化学
病理
疾病
基因
作者
Bruno P. Imbimbo,Elda Del Giudice,Davide Colavito,Antonello D’Arrigo,Maurizio Dalle Carbonare,Gino Villetti,Fabrizio Facchinetti,Roberta Volta,Vladimiro Pietrini,M. F. Baroc,Lutgarde Serneels,Bart De Strooper,Alberta Leon
标识
DOI:10.1124/jpet.107.129007
摘要
Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of gamma-secretase, the enzymatic complex responsible for the formation of beta-amyloid (Abeta). 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a new gamma-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Abeta pathology in Tg2576 transgenic mice. Twenty-eight animals of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. Compared with controls, CHF5074 treatment significantly reduced the area occupied by plaques and the number of plaques in cortex (-52.2 +/- 5.6%, p = 0.0003 and -48.9 +/- 6.6%, p = 0.0004, respectively) and hippocampus (-76.7 +/- 6.4%, p = 0.004 and -66.2 +/- 10.3%, p = 0.037, respectively). Biochemical analysis confirmed the histopathological measures, with CHF5074-treated animals showing reduced total brain Abeta40 (-49.2 +/- 9.2%, p = 0.017) and Abeta42 (-43.5 +/- 9.7%, p = 0.027) levels. In a human neuroglioma cell line expressing Swedish mutated form of amyloid precursor protein (H4swe), CHF5074 reduced Abeta42 and Abeta40 secretion, with an IC50 of 3.6 and 18.4 microM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 +/- 0.4 microM). At 5 microM, no effects were observed on Notch intracellular cleavage in human embryonic kidney 293swe cells. CHF5074 was well tolerated by Tg2576 mice. No abnormal findings were observed upon histopathological examination of the gastrointestinal tract, indicating the absence of COX-related toxicity. Semiquantitative histochemical evaluation of goblet cells in the ileum of vehicle- and CHF5074-treated animals yielded similar results, suggesting no effects on Notch pathway. CHF5074 is therefore a promising therapeutic agent for Alzheimer's disease.
科研通智能强力驱动
Strongly Powered by AbleSci AI