PRESENILIN 1 IS A COMPONENT OF THE ADHERENS JUNCTIONS

早老素1 （PS1）是一种参与家族性阿尔茨海默病（FAD）发展的完整膜蛋白。PS1在细胞内被加工成N端和c端片段。典型的钙粘蛋白是I型跨膜糖蛋白，控制细胞粘附和细胞识别的关键事件。基于钙粘蛋白的细胞粘附是由连环蛋白介导的，连环蛋白是连接表面钙粘蛋白和皮质细胞骨架的细胞质蛋白。我们使用共聚焦显微镜显示，在细胞培养中，PS1积聚在细胞-细胞接触部位。在这些位点，PS1与钙粘蛋白黏着连接的组分共定位，并与皮质细胞骨架相连。两种PS1片段都与钙粘蛋白黏附系统的组分形成复合物，包括e -钙粘蛋白、β -连环蛋白、γ -连环蛋白和α -连环蛋白。此外，PS1片段在E-cadherin和β - catenin的一个复合体中被发现。PS1与细胞表面e -钙粘蛋白形成复合物，并在上皮组织中集中于细胞-细胞接触部位。总之，这些数据表明PS1结合到钙粘蛋白/连环蛋白粘附系统中，它可能在细胞-细胞粘附和识别中起作用。在大脑中，PS1片段与钙粘蛋白形成复合物，钙粘蛋白是突触的已知成分。因此，PS1突变可能通过破坏钙粘蛋白为基础的细胞-细胞相互作用而在FAD中起作用。基于这些发现，我们建议定义PS1与基于钙粘蛋白的粘附系统的其他组分之间的结合，并探索PS1 FAD突变体如何影响这些结合。我们还将研究PS1是否在钙粘蛋白-细胞粘附中起作用，并确定FAD突变对PS1功能的影响。最后，我们将检查PS1是否是突触中钙粘蛋白/连环蛋白装置的一部分。

Presenilin1 (PS1) is an integral membrane protein involved in the development of familial Alzheimer disease (FAD). PS1 is processed intracellularly into N and C-terminal fragments. Classic cadherins are type I transmembrane glycoproteins that control critical events in cell-cell adhesion and recognition. Cadherin-based cell adhesion is mediated by catenins, which are cytosolic proteins that link surface cadherin to the cortical cytoskeleton. We used confocal microscopy to show that in cell cultures PS1 accumulates at cell-cell contact sites. At these sites, PS1 colocalizes with components of the cadherin-based adherens junctions and is linked to the cortical cytoskeleton. Both PS1 fragments form complexes with components of the cadherin-based adhesion system including E-cadherin, beta- catenin, gamma-catenin, and alpha-catenin. Furthermore, PS1 fragments are found in a single complex with E-cadherin and beta- catenin. PS1 forms complexes with cell surface E-cadherin, and in epithelial tissue it concentrates at cell-cell contact sites. Together, these data show that PS1 incorporates into the cadherin/catenin adhesion system where it probably functions in cell-cell adhesion and recognition. In the brain, PS1 fragments form complexes with cadherins which are known components of the synapse. Thus, PS1 mutations may act in FAD through disruption of cadherin-based cell-cell interactions. Based on these findings, we propose to define the bindings between PS1 and other components of the cadherin-based adhesion system and to explore how PS1 FAD mutants affect these bindings. We will also examine whether PS1 functions in cadherin-based cell-cell adhesion, and define the effects of FAD mutations on PS1 function. Finally, we will examine whether PS1 is part of the cadherin/catenin apparatus at the synapse.