STRUCTURE, EXPRESSION AND FUNCTION OF THE APP CHONDROITIN SULFATE PROTEOGLYCAN

APP 硫酸软骨素蛋白聚糖的结构、表达和功能

• 批准号: 6234067
• 负责人: NIKOLAOS K ROBAKIS
• 金额: $ 14.08万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234067
• 关键词: Alzheimer's disease; amyloid proteins; brain mapping; carbohydrate structure; cell adhesion; chondroitin sulfates; collagen; cytoskeleton; developmental genetics; developmental neurobiology; fibronectins; gene expression; human tissue; intermolecular interaction; laboratory rat; laminin; neural cell adhesion molecules; oligosaccharides; protein structure function; proteoglycan; secretory protein; tissue /cell culture

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.

神经炎斑块核心和脑血管炎斑块核心的主要成分 阿尔茨海默病（AD）的淀粉样蛋白作为至少 三种不同的前体蛋白，称为APP 695、APP 751、APP 770。 APP通常通过至少两种途径代谢：一种途径涉及 在A β P序列内切割，从而防止形成 淀粉样肽 第二种“淀粉样蛋白生成”途径导致 淀粉样肽的产生。 最近的遗传学研究表明， APP基因中导致氨基酸取代的某些突变 可能导致家族性AD。 然而，目前尚不清楚这些 突变通过增加淀粉样蛋白肽的产生或通过 改变APP蛋白的生物学功能。 由于结构 生物分子的元素定义了它的生物学功能和它的 代谢途径，确定的结构特征， APP对于阐明其在AD发展中的作用是重要的。 我们实验室的研究表明，APP作为一种蛋白质的核心蛋白存在。 硫酸软骨素蛋白聚糖（CSPG），表观分子大小 140至250 kDa，由神经胶质细胞系分泌。 大部分的秘密 连接蛋白II形式APP以蛋白聚糖形式存在。 我们也得到 有证据表明APP蛋白聚糖存在于人脑中， 神经母细胞瘤细胞 蛋白聚糖是具有重要生物活性的分子， 功能包括细胞粘附和迁移，细胞-细胞通讯， 调节生长因子活性和神经模式。 功能障碍 CSPG形式的APP可能参与神经元变性 在AD中观察 我们发现了两种潜在的硫酸软骨素 糖胺聚糖（CSG）附着位点与N- APP的A β P序列的末端和分泌酶切割位点， 表明CSG链可能影响APP的蛋白水解， 生产AbetaP。 在这里，我们建议确定附着位点 和CSG链的长度，碳水化合物残基的结构 研究了APP CSPG在细胞粘附中的作用。 此外 我们将研究这种新的APP形式在正常和AD中的表达， 脑及其发育调控的研究进展。