β淀粉样蛋白38和β淀粉样蛋白42的生成受到家族性阿尔茨海默病相关早老素突变和γ-分泌酶调节的独立且不同的影响。

Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation.

作者信息

Page Richard M, Baumann Karlheinz, Tomioka Masanori, Pérez-Revuelta Blanca I, Fukumori Akio, Jacobsen Helmut, Flohr Alexander, Luebbers Thomas, Ozmen Laurence, Steiner Harald, Haass Christian

机构信息

Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany.

出版信息

J Biol Chem. 2008 Jan 11;283(2):677-83. doi: 10.1074/jbc.M708754200. Epub 2007 Oct 24.

DOI:10.1074/jbc.M708754200

PMID:17962197

Abstract

Alzheimer disease amyloid beta-peptide (Abeta) is generated via proteolytic processing of the beta-amyloid precursor protein by beta- and gamma-secretase. Gamma-secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal anti-inflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid Abeta(42) and concomitantly increase the levels of the rather benign Abeta(38). Here we show that Abeta(42) and Abeta(38) generation occur independently from each other. The amount of Abeta(42) produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of gamma-secretase, appeared to correlate with the respective age of onset in patients. However, Abeta(38) levels did not show a negative correlation with the age of onset. Modulation of gamma-secretase activity by sulindac sulfide reduced Abeta(42) in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of Abeta(42) or only rather subtle effects. Strikingly, even the mutations that showed no effect on Abeta(42) levels allowed a robust increase of Abeta(38) upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase Abeta(42) and to decrease Abeta(38). For mutants that predominantly produce Abeta(42), the ability of fenofibrate to further increase Abeta(42) levels became diminished, whereas Abeta(38) levels were altered to varying extents for all mutants analyzed. Thus, we conclude that Abeta(38) and Abeta(42) production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the Abeta(42)-lowering capacity of gamma-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to gamma-secretase modulators.

摘要

阿尔茨海默病β淀粉样肽（Aβ）是由β淀粉样前体蛋白经β-和γ-分泌酶进行蛋白水解加工产生的。γ-分泌酶可被选择性抑制剂阻断，但也可被包括舒林酸硫化物在内的一类非甾体抗炎药调节。这些药物选择性地减少易于聚集的42个氨基酸的Aβ（42）的生成，并同时增加相对无害的Aβ（38）的水平。在此我们表明，Aβ（42）和Aβ（38）的生成是相互独立发生的。在γ-分泌酶的催化亚基早老素（PS）1中表达10种不同的家族性阿尔茨海默病（FAD）相关突变的细胞所产生的Aβ（42）量，似乎与患者各自的发病年龄相关。然而，Aβ（38）水平与发病年龄并未呈现负相关。舒林酸硫化物对γ-分泌酶活性的调节在野生型PS1以及两种FAD相关的PS1突变（M146L和A285V）的情况下降低了Aβ（42）。其余8种PS1 FAD突变体要么没有降低Aβ（42），要么只有相当细微的影响。引人注目的是，即使是对Aβ（42）水平没有影响的突变，在用舒林酸硫化物处理后也能使Aβ（38）显著增加。对于非诺贝特也有类似的观察结果，非诺贝特是一种已知会增加Aβ（42）并降低Aβ（38）的化合物。对于主要产生Aβ（42）的突变体，非诺贝特进一步增加Aβ（42）水平的能力减弱，而对于所有分析的突变体，Aβ（38）水平都有不同程度的改变。因此，我们得出结论，Aβ（38）和Aβ（42）的产生并不相互依赖。使用一种独立的非甾体抗炎药衍生物，我们在PS1以及PS2上获得了类似的结果。这些体外结果在表达PS2 N141I FAD突变体的转基因小鼠的体内实验中得到了证实。因此，我们的发现对用于筛选γ-分泌酶调节剂降低Aβ（42）能力的转基因小鼠模型的选择具有重要意义。此外，患有某些PS突变的人类患者可能对γ-分泌酶调节剂无反应。