Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.
Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease.
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DOI：
10.1007/s00401-012-1062-9
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发表时间：
2013-02
影响因子：
12.7
通讯作者：
Lleó A
中科院分区：
文献类型：
--
作者：
Pera M;Alcolea D;Sánchez-Valle R;Guardia-Laguarta C;Colom-Cadena M;Badiola N;Suárez-Calvet M;Lladó A;Barrera-Ocampo AA;Sepulveda-Falla D;Blesa R;Molinuevo JL;Clarimón J;Ferrer I;Gelpi E;Lleó A
常染色体显性阿尔茨海默病（ADAD）是一种由淀粉样前体蛋白（APP）或早老素（PSEN）基因突变引起的遗传性疾病。来自ADAD家族的研究对于支持阿尔茨海默病（AD）的淀粉样蛋白级联假说至关重要，淀粉样蛋白级联假说是目前在散发性AD（SAD）中开发基于淀粉样蛋白的疾病修饰疗法的基础。然而，ADAD中CNS中APP加工的病理变化是否与SAD中观察到的相似仍不清楚。在这项研究中，我们测量了携带APP或PSEN 1突变的ADAD受试者（n = 18）、SAD患者（n = 27）和年龄匹配的对照组（n = 22）脑样本中的β位点APP裂解酶（BACE）蛋白水平和活性、APP和APP C末端片段。我们还测量了携带PSEN 1突变个体（10名突变携带者和7名非携带者对照）、SAD患者（n = 32）和年龄匹配对照（n = 11）CSF中的sAPPβ和BACE蛋白水平以及BACE活性。我们发现，在大脑中，ADAD模式的特征是APP β-C-末端片段（β-CTF）水平增加，尽管BACE蛋白水平或活性没有变化。相比之下，大脑中SAD模式的主要特征是BACE水平和活性增加，APP β-CTF蓄积少于ADAD。在CSF中，未发现组间BACE活性或表达或sAPPβ水平存在差异。综上所述，这些数据表明SAD和ADAD中慢性Aβ产生/清除失衡的病理生理学事件不同。在设计AD干预试验时应考虑这些差异。本文的在线版本（doi：10.1007/s 00401 -012-1062-9）包含补充材料，可供授权用户使用。
Autosomal-dominant Alzheimer disease (ADAD) is a genetic disorder caused by mutations in Amyloid Precursor Protein (APP) or Presenilin (PSEN) genes. Studies from families with ADAD have been critical to support the amyloid cascade hypothesis of Alzheimer disease (AD), the basis for the current development of amyloid-based disease-modifying therapies in sporadic AD (SAD). However, whether the pathological changes in APP processing in the CNS in ADAD are similar to those observed in SAD remains unclear. In this study, we measured β-site APP-cleaving enzyme (BACE) protein levels and activity, APP and APP C-terminal fragments in brain samples from subjects with ADAD carrying APP or PSEN1 mutations (n = 18), patients with SAD (n = 27) and age-matched controls (n = 22). We also measured sAPPβ and BACE protein levels, as well as BACE activity, in CSF from individuals carrying PSEN1 mutations (10 mutation carriers and 7 non-carrier controls), patients with SAD (n = 32) and age-matched controls (n = 11). We found that in the brain, the pattern in ADAD was characterized by an increase in APP β-C-terminal fragment (β-CTF) levels despite no changes in BACE protein levels or activity. In contrast, the pattern in SAD in the brain was mainly characterized by an increase in BACE levels and activity, with less APP β-CTF accumulation than ADAD. In the CSF, no differences were found between groups in BACE activity or expression or sAPPβ levels. Taken together, these data suggest that the physiopathological events underlying the chronic Aβ production/clearance imbalance in SAD and ADAD are different. These differences should be considered in the design of intervention trials in AD. The online version of this article (doi:10.1007/s00401-012-1062-9) contains supplementary material, which is available to authorized users.
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影响因子：
5.3
作者：
Berezovska, O;Lleo, A;Hyman, BT
通讯作者：
Hyman, BT
影响因子：
12.7
作者：
Alafuzoff, Irina;Pikkarainen, Maria;Kretzschmar, Hans
通讯作者：
Kretzschmar, Hans
DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
DOI：
10.1073/pnas.0908953107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Jiang, Ying;Mullaney, Kerry A.;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
3.7
作者：
Arnold, Steven E.;Hyman, Bradley T.;Van Hoesen, Gary W.
通讯作者：
Van Hoesen, Gary W.