Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein
Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein
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DOI：
10.1523/jneurosci.0364-05.2005
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发表时间：
2005-03-16
影响因子：
5.3
通讯作者：
Hyman, BT
中科院分区：
文献类型：
--
作者：
Berezovska, O;Lleo, A;Hyman, BT
早老素1（PS1）是γ-分泌酶复合物的关键组分，γ-分泌酶复合物是从淀粉样前体蛋白（APP）切割淀粉样β（A β）的酶活性。在PS1分子中分布的100多个突变与常染色体显性遗传家族性阿尔茨海默病（FAD）有关。所有这些突变导致相似的表型：A β（42）与A β（40）的比例增加，斑块沉积增加，发病年龄较早。我们使用最近开发的显微镜方法，荧光寿命成像显微镜，监测PS1的N和C末端在完整的细胞之间的相对分子距离。结果表明，位于PS 1中间区N、C端的FAD连锁错义突变和第9外显子缺失突变均以类似的方式改变PS 1 N、C端的空间关系，增加了两个表位的接近性。这种作用与用降低A β（42）的非甾体抗炎药（NSAID）治疗所观察到的作用相反（Lleo等人，2004年b）。因此，用高剂量NSAID治疗M146 L PS1过表达神经元在一定程度上抵消了与突变相关的构象变化。此外，通过监测PS1环表位和APP C末端之间的相对距离，我们证明了FAD PS1突变也与PS1 - APP复合物构型的一致变化相关。非致病性E318 G PS1多态性对PS1 N端- C端邻近或PS1 - APP相互作用没有影响。我们建议，我们观察到的构象变化，因此可能提供了一个共享的分子机制FAD的发病机制所造成的广泛的PS1突变。
Presenilin 1 (PS1) is a critical component of the gamma-secretase complex, an enzymatic activity that cleaves amyloid beta(A beta) from the amyloid precursor protein (APP). More than 100 mutations spread throughout the PS1 molecule are linked to autosomal dominant familial Alzheimer's disease (FAD). All of these mutations lead to a similar phenotype: an increased ratio of A beta(42) to A beta(40), increased plaque deposition, and early age of onset. We use a recently developed microscopy approach, fluorescence lifetime imaging microscopy, to monitor the relative molecular distance between PS1 N and C termini in intact cells. Weshow that FAD-linked missense mutations located near the N and C termini, in the mid-region of PS1, and the exon 9 deletion mutation all change the spatial relationship between PS 1 N and C termini in a similar way, increasing proximity of the two epitopes. This effect is opposite of that observed by treatment with A beta(42)-lowering nonsteroidal anti-inflammatory drugs (NSAIDs) (Lleo et al., 2004b). Accordingly, treatment of M146L PS1-overexpressing neurons with high-dose NSAIDs somewhat offsets the conformational change associated with the mutation. Moreover, by monitoring the relative distance between a PS1 loop epitope and the APP C terminus, we demonstrate that the FAD PS1 mutations are also associated with a consistent change in the configuration of the PS1 - APP complex. The nonpathogenic E318G PS1 polymorphism had no effect on PS1 N terminus - C terminus proximity or PS1 - APP interactions. We propose that the conformational change we observed may therefore provide a shared molecular mechanism for FAD pathogenesis caused by a wide range of PS1 mutations.