Pradier L, Carpentier N, Delalonde L, Clavel N, Bock M D, Buée L, Mercken L, Tocqué B, Czech C
Gene Medicine Department, Rhône-Poulenc Rorer, Vitry, France.
Neurobiol Dis. 1999 Feb;6(1):43-55. doi: 10.1006/nbdi.1998.0212.
Mutations in presenilin 1 and presenilin 2 (PS1 and PS2, respectively) genes cause the large majority of familial forms of early-onset Alzheimer's disease. The physical interaction between presenilins and APP has been recently described using coimmunoprecipitation. With a similar technique, we confirmed this interaction and have mapped the interaction domains on both PS2 and APP. Using several carboxy-terminal truncated forms of PS2, we demonstrated that the hydrophilic amino terminus of PS2 (residues 1 to 87, PS2NT) was sufficient for interaction with APP. Interestingly, only a construct with a leader peptide for secretion (SecPS2NT) and not its cytosolic counterpart was shown to interact with APP. For APP, we could demonstrate interaction of PS2 with the last 100 but not the last 45 amino acids of APP, including therefore the A beta region. Accordingly, SecPS2NT is capable of binding to A beta-immunoreactive species in conditioned medium. In addition, a second region in the extracellular domain of APP also interacted with PS2. Comparable results with PS1 indicate that the two presenilins share similar determinants of binding to APP. Confirming these results, SecPS2NT is able to inhibit PS1/APP interaction. Such a competition makes it unlikely that the PS/APP interaction results from nonspecific aggregation of PS in transfected cells. The physical interaction of presenilins with a region encompassing the A beta sequence of APP could be causally related to the misprocessing of APP and the production of A beta1-42.
早老素1和早老素2（分别为PS1和PS2）基因的突变导致了绝大多数早发性阿尔茨海默病的家族形式。最近通过免疫共沉淀描述了早老素与淀粉样前体蛋白（APP）之间的物理相互作用。使用类似技术，我们证实了这种相互作用，并绘制了PS2和APP上的相互作用结构域。通过使用PS2的几种羧基末端截短形式，我们证明PS2的亲水性氨基末端（第1至87位氨基酸，PS2NT）足以与APP相互作用。有趣的是，只有带有分泌前导肽的构建体（SecPS2NT）而非其胞质对应物显示能与APP相互作用。对于APP，我们可以证明PS2与APP的最后100个氨基酸而非最后45个氨基酸相互作用，因此包括Aβ区域。相应地，SecPS2NT能够与条件培养基中的Aβ免疫反应性物质结合。此外，APP细胞外结构域中的第二个区域也与PS2相互作用。与PS1的类似结果表明，这两种早老素在与APP结合的决定因素方面具有相似性。证实这些结果的是，SecPS2NT能够抑制PS1/APP相互作用。这种竞争使得PS/APP相互作用不太可能是由转染细胞中PS的非特异性聚集引起的。早老素与包含APP的Aβ序列的区域之间的物理相互作用可能与APP的错误加工和Aβ1-42的产生存在因果关系。
