Mechanisms of beta-APP Processing in the Brain

基于其他细胞间相互作用系统的先例，我们提出了一个假设，即β -淀粉样蛋白前体蛋白（β - app）和早老素1或2 （PS-1或2）的一种或多种形式通常可能是细胞间近胞碱信号系统的组成部分(1)。我们已经证明B-APP和PS-1和2可以在细胞表面表达，β - app和早老素在细胞间相互作用，这种相互作用导致信号传导，最后，我们假设的最关键测试：AB是β - app与PS-1或PS-2跨细胞结合的结果。在这个应用中，我们扩展了我们最初的假设，提出β - app和PS的细胞间结合也是β - app在α位点切割所必需的。PS-1似乎不仅能调节γ -分泌酶活性，还能诱导α -分泌酶活性(2)。到目前为止，还没有详细的机制描述这是如何发生的。我们认为，在β - app与PS-1或PS-2相互作用后，要么通过内吞途径产生β，要么通过细胞表面机制运作，β - app被α分泌酶裂解，从而阻止了β的形成。然后β - app的α -裂解外畴脱落，可能引发细胞-细胞脱粘，正如对ephrin的描述(3)。因此，该模型提出，为了发生α -裂解，β - app必须首先在细胞间与PS-1或PS-2相互作用。我们的具体目标是：1。研究β - app的裂解和外胞结构域脱落是否需要β - app与PS-1或PS-2结合介导的特异性细胞-细胞相互作用，并研究可溶性β - app产生与β产生的定量关系。2. 研究β - app与PS细胞间结合后细胞间接触区域的事件，以激活β - app的α分泌酶蛋白水解和接触细胞可能的脱离。3. 探讨β - app:PS细胞间结合诱导的生化信号是否为β - app α裂解所必需。

We had proposed a hypothesis based on precedents in other systems of an intercellular interaction crucial to development between single membrane spanning and seven membrane spanning integral proteins, that one or more forms of the Beta-amyloid precursor protein (Beta-APP) and Presenilin 1 or 2 (PS-1 or 2) may normally be components of an intercellular juxtacrine signaling system (1). We have shown that B-APP and PS-1 and 2 are expressible at the cell surface, that Beta-APP and the presenilins interact intercellularly, that this interaction results in signaling and finally, the most critical test of our hypothesis: that AB is produced as a result of the transcellular binding of Beta-APP with PS-1 or PS-2. In this application we are extending our original hypothesis to propose that intercellular binding of Beta-APP and PS is also required for the cleavage of Beta-APP at the alpha-site. PS-1 appears to regulate not only distinct gamma-secretase activities, but inducible alpha-secretase activity as well (2). No detailed mechanisms have so far been described as to how this might happen. We propose that after cell-cell interaction of Beta-APP with PS-1 or PS-2, either ABeta may be produced via an endocytic pathway, or alternatively, a cell-surface mechanism operates and Beta-APP is cleaved by alpha-secretase, precluding the formation of ABeta. The alpha-cleaved ectodomain of Beta-APP is then shed, possibly triggering a cell-cell de-adhesion, as has been described for the ephrins (3). Therefore, this model proposes that for alpha-cleavage to occur, Beta-APP must first interact intercellularly with PS-1 or PS-2. Our specific aims are: 1. To investigate whether or-cleavage of Beta-APP and ectodomain shedding requires the prior specific cell-cell interaction mediated by the binding of Beta-APP with either PS-1 or PS-2 and to investigate the quantitative relationship of soluble Beta-APP production to ABeta production. 2. To investigate events at regions of cell-cell contact following the intercellular binding of Beta-APP with PS for the activation of alpha-secretase proteolysis of Beta-APP and the possible detachment of the contacting cells. 3. To investigate whether the biochemical signals that are induced by Beta-APP:PS intercellular binding are required for the alpha cleavage of Beta-APP.