STRUCTURE, EXPRESSION AND FUNCTION OF THE APP CHONDROITIN SULFATE PROTEOGLYCAN

神经炎斑块核心和脑血管的主要成分 阿尔茨海默病(AD)的淀粉样蛋白至少是一种成分 三种不同的前体蛋白，分别称为APP695、APP751、APP770。 APP通常至少通过两条途径代谢：一条途径涉及 AbetaP序列内的切割，从而防止形成 淀粉样多肽。第二个“淀粉样变性”途径导致 淀粉样多肽的产生。最近的遗传学研究表明， 导致氨基酸替换的APP基因的某些突变 可能导致家族性AD。然而，目前仍不清楚这些是否 突变通过增加淀粉样多肽的产生或通过 改变APP蛋白的生物学功能。由于结构上的 生物分子的元素既定义了它的生物功能，也定义了它的 代谢途径，测定其结构特征 APP对于阐明其在AD发生发展中的作用具有重要意义。 我们实验室的研究表明，APP以核心蛋白的形式存在 硫酸软骨素蛋白多糖(CSPG)，表观分子大小不等 从140 kDa到250 kDa，由神经胶质细胞株分泌。大部分的秘密 Nexin II形式的APP以蛋白多糖的形式存在。我们还获得了 有证据表明APP蛋白多糖存在于人脑和 神经母细胞瘤细胞。蛋白多糖是具有重要生物学意义的分子。 包括细胞黏附和迁移、细胞间通讯、 生长因子活性的调节和神经构型。功能障碍 CSPG形式的APP可能与神经元变性有关 在公元后观察到。我们发现了两种潜在的硫酸软骨素 糖胺多聚糖(CSG)附着位置靠近N- APP的AbetaP序列和分泌酶裂解位点的末端， 提示CSG链可能影响APP和APP的蛋白分解。 AbetaP的生产。在这里，我们建议确定附着点 和CSG链的长度，碳水化合物残基的结构 APP的附着和APP CSPG在细胞黏附中的作用。此外 我们将研究这种新的APP形式在正常和AD中的表达 脑及其在大鼠脑中的发育调控。

The major component of the neuritic plaque cores and cerebrovascular amyloid of the Alzheimer's disease (AD) exists as a component of at least three distinct precursor proteins, referred to as APP695, APP751, APP770. APP is normally metabolized by at least two pathways: one pathway involves cleavage within the AbetaP sequence, thus preventing formation of the amyloid peptide. The second "amyloidogenic" pathway results in the production of the amyloid peptide. Recent genetic studies showed that certain mutations in the APP gene that result in amino acid substitutions may cause Familial AD. However, it is still not clear whether these mutations cause AD by increasing production of the amyloid peptide or by altering the biological function of the APP protein. Since the structural elements of a biomolecule define both its biological function and its metabolic pathway, determination of the structural characteristics of the APP is important for the elucidation of its role in the development of AD. Research in our laboratory showed that APP exists as the core protein of a chondroitin sulfate proteoglycan (CSPG), ranging in apparent molecular size from 140 to 250 kDa, secreted by a glial cell line. Most of the secreted nexin II form oa APP occurs in the proteoglycan form. We also obtained evidence that the APP proteoglycan is present in human brain and neuroblastoma cells. Proteoglycans are molecules with important biological functions including cell adhesion and migration, cell-cell communication, modulation of growth factor activities and neural patterning. Dysfunction of the CSPG form of APP may contribute to the neuronal degeneration observed in AD. We find two potential chondroitin sulfate glycosaminoglycan (CSG) attachment sites in close proximity to both the N- terminus of the AbetaP sequence of APP and the secretase cleavage site, suggesting that the CSG chains may affect the proteolysis of APP and production of AbetaP. Here we propose to determine the attachment sites and length of the CSG chains, the structure of the carbohydrate residues attached to APP and the role of the APP CSPG in cell adhesion. In addition we will examine the expression of this novel APP form in normal and AD brains and its developmental regulation in rat brain.