Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction.
Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction.
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DOI：
10.1002/ana.22343
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发表时间：
2011-06
影响因子：
11.2
通讯作者：
Suzuki, Toshiharu
中科院分区：
文献类型：
--
作者：
Hata, Saori;Fujishige, Sayaka;Araki, Yoichi;Taniguchi, Miyako;Urakami, Katsuya;Peskind, Elaine;Akatsu, Hiroyasu;Araseki, Masahiko;Yamamoto, Kazuo;Martins, Ralph N.;Maeda, Masahiro;Nishimura, Masaki;Levey, Allan;Chung, Kathryn A.;Montine, Thomas;Leverenz, James;Fagan, Anne;Goate, Alison;Bateman, Randall;Holtzman, David M.;Yamamoto, Tohru;Nakaya, Tadashi;Gandy, Sam;Suzuki, Toshiharu
家族性阿尔茨海默病（FAD）最常见的发病机制涉及由于早老素1 （PS1）基因突变导致γ-分泌酶对淀粉样蛋白前体蛋白（APP）的错误加工（或替代加工）。这种错误处理/替代处理导致次要γ-分泌酶反应产物（a β42）与主要反应产物（a β40）的水平之比增加。虽然不存在PS1突变，但散发性阿尔茨海默病（SAD）中也观察到Aβ42/40比值的改变，这些比值的改变显然反映了Aβ42作为淀粉样蛋白的沉积。采用定量准确的免疫沉淀-质谱法，我们分析了不同临床人群脑脊液（CSF）中由APP和一种不相关的蛋白alcadein （Alc）加工产生的肽产物。Alc由相同的APP α-分泌酶和γ-分泌酶代谢，产生我们称之为p3-Alcα的片段，因为p3-Alcα肽和APP的p3片段平行发生。与a β一样，产生主要和次要的p3-Alcαs。我们研究了p3-Alcα在不同临床人群中的替代加工。我们之前报道过，在表达fad连锁PS1突变体的细胞调节的培养基中，a β42/40比值的变化与p3-Alcα[次要/主要]比值的水平呈线性协方差关系。我们研究了3组人脑脊液中p3-Alcα的形态（n = 158）：老年无痴呆对照；轻度认知障碍（MCI）受试者临床痴呆评分（CDR）为0.5；CDR为1.0的SAD受试者；及其他神经系统疾病（OND）对照受试者。脑脊液p3-Alcα微小变异p3-Alcα38在MCI或SAD患者中升高（p < 0.05），这取决于数据是作为单一队列合并分析还是作为3个单独队列单独分析。这些结果表明，一些SAD可能涉及多种γ-分泌酶底物的交替加工，从而提高了SAD的分子发病机制可能涉及γ-分泌酶功能障碍的可能性。
The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid. Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alcα because of the parallel genesis of p3-Alcα peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alcαs are generated. We studied the alternative processing of p3-Alcα in various clinical populations. We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alcα [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alcα in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alcα variant, p3-Alcα38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.
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影响因子：
4.8
作者：
Buxbaum, JD;Liu, KN;Black, RA
通讯作者：
Black, RA
影响因子：
82.9
作者：
Kukar, T;Murphy, MP;Golde, TE
通讯作者：
Golde, TE
影响因子：
4.8
作者：
Araki, Y;Tomita, S;Suzuki, T
通讯作者：
Suzuki, T
DOI：
10.1073/pnas.96.7.3922
发表时间：
1999-03-30
影响因子：
11.1
作者：
Lammich, S;Kojro, E;Fahrenholz, F
通讯作者：
Fahrenholz, F
影响因子：
4.8
作者：
Hata, Saori;Fujishige, Sayaka;Suzuki, Toshiharu
通讯作者：
Suzuki, Toshiharu