IDENTIFICATION AND CHARACTERIZATION OF FIRST MESSENGERS THAT REGULATE APP

长期以来，阿尔茨海默病患者大脑中的β-淀粉样蛋白(Abeta)沉积一直被认为是阿尔茨海默病(AD)病理进展的潜在致病因素。在过去的10年里，对导致Abeta产生的蛋白降解事件的表征一直是严格而详尽的研究对象。现在人们知道，淀粉样前体蛋白(APR)由一组被称为分泌酶的酶处理，最终是AS解放的基础。随着人们对这些酶的了解越来越多，越来越清楚的是，它们可能有许多底物，抑制它们可能会有多种生物学效应。这一提议的中心问题是，哪些细胞间信号调节 APP的割裂。APP的加工过程与其他跨膜蛋白相似。其中最值得注意的是存在于APP和Notch之间的竞争。Notch与其任何同源配体(即Delta、锯齿状、锯齿状)的结合会导致Notch受体的断裂和胞外结构域的脱落。在这一受调控的步骤之后，通过受调控的膜内加工(RIP)进行切割，导致Notch细胞内域(NICD)的释放。然后，NiCd被转移到细胞核，在那里它起到转录调节的作用。对于Notch，是配体的结合激活了加工分泌酶。 APP裂解的特异性激活可能是通过配体与APP的结合(也可能是配体与异源受体的结合)来诱导的。具体目标如下：1)确定与APP结合并以与Notch加工一致的方式调节切割的配体的身份；2)确定生长因子受体与 3)阐明APP配体或生长因子受体调控APP切割的潜在分子途径；以及4)确定在对照组和阿尔茨海默病组织中调节APP加工的第一信使通路(包括APP配体和异源受体及其配体)的水平和分布。

The deposition of beta-amyloid (Abeta) in the Alzheimer's brain has long been regarded as a potential causative agent in the progression of Alzheimer's disease (AD) pathology. Over the past 10 years, characterization of the proteolytic events leading to Abeta generation has been the object of rigorous and exhaustive investigation. It is now understood that processing of the amyloid precursor protein (APR) by a group of enzymes known as the secretases ultimately underlies the liberation of AS. As more is known about these enzymes, it becomes increasingly clear that they likely have many substrates and inhibiting them may have multiple biological effects. The central question of this proposal is which intercellular signals regulate regulate the cleavage of APP. The processing of APP resembles that of other transmembrane proteins. The most notable among these is that which exists between APP and Notch. Binding of Notch to any of its cognate ligands (ie delta, jagged, serrate) results incleavage of the Notch receptor and shedding of the extracellular domain. This regulated step is followed by cleavage by through regulated intramembranous processing (RIP), leading to the liberation of the Notch Intracellular Domain (NICD). NICD is then translocated to the nucleus where it acts as regulator of transcription. With Notch, it is binding of ligand that activates the processing secretases. It appears likely that specific activation of APP cleavage may be induced by the binding of ligand to APP (and, perhaps ligand binding to heterologous receptors). The Specific Aims are as follows: 1) Determine the identity of ligands that bind APP and regulate cleavage in a manner consistent with Notch processing; 2) Determine the potential for growth-factor receptors to regulate cleavage of APP; 3) Elucidate the potential molecular pathways through which APP ligands or growth-factor receptors regulate APP cleavage; and, 4) Determine the levels and distribution of first messenger pathways (including APP ligands and heterologous receptors and their ligands) that regulate APP processing in control and Alzheimer tissue.