Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor
Dynamics of β-amyloid reductions in brain, cerebrospinal fluid, and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor
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DOI：
10.1124/jpet.104.075408
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Felsenstein, KM
中科院分区：
文献类型：
--
作者：
Barten, DM;Guss, VL;Felsenstein, KM
γ-分泌酶抑制剂是开发阿尔茨海默病（AD）治疗剂的一种有前景的方法。γ-分泌酶抑制剂减少脑β-淀粉样肽（Abeta），其被认为是AD病因学的主要贡献者。过表达人β-淀粉样前体蛋白（APP）的转基因小鼠是研究无斑块和有斑块动物中γ-分泌酶抑制剂对Abeta变化动力学的有价值的模型。BMS-299897 2-[（1 R）-1-[[（4-氯苯基）磺酰基]（2，5-二氟苯基）氨基]乙基]-5-氟苯丙酸（一种γ-分泌酶抑制剂）显示幼龄转基因小鼠脑、脑脊液（CSF）和血浆中的A β呈剂量和时间依赖性降低，脑和CSF A β水平之间具有显著相关性。由于CSF和脑间质液在成分和位置上是不同的区室，因此不能假设这种相关性。相比之下，在长达2周的治疗后，在脑中斑块A β没有可测量的变化的情况下，斑块中A β大量积累的老年转基因小鼠显示CSF A β减少。因此，CSF Abeta水平是在存在或不存在斑块的情况下中枢神经系统中γ-分泌酶活性的有价值的测量。还使用转基因小鼠来检查Notch抑制引起的潜在副作用。BMS-299897在体外预防APP裂解的有效性是Notch的15倍。在BMS-299897处理的小鼠中未观察到CD 8+胸腺细胞或肠杯状细胞成熟的变化，表明γ-分泌酶抑制剂可能降低脑A β而不引起Notch介导的毒性。
gamma-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer's disease (AD). gamma-Secretase inhibitors reduce brain beta-amyloid peptide (Abeta), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human beta-amyloid precursor protein (APP) are valuable models to examine the dynamics of Abeta changes with gamma-secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl) sulfony](2,5-difluorophenyl) amino] ethyl]-5-fluorobenzenepropanoic acid, a gamma-secretase inhibitor, showed dose- and time dependent reductions of Abeta in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF Abeta levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of Abeta in plaques showed reductions in CSF Abeta in the absence of measurable changes in plaque Abeta in the brain after up to 2 weeks of treatment. Hence, CSF Abeta levels were a valuable measure of gamma-secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in the maturation of CD8+ thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for gamma-secretase inhibitors to reduce brain Abeta without causing Notch-mediated toxicity.