Sandbrink R, Mönning U, Masters C L, Beyreuther K
Center for Molecular Biology Heidelberg (ZMBH), University of Heidelberg, Germany.
Gerontology. 1997;43(1-2):119-31. doi: 10.1159/000213840.
The Alzheimer's beta A4-amyloid protein precursor (APP) and the APP-like proteins (APLPs) are transmembrane glycoproteins with a similar modular domain structure. Alternatively spliced exons found in both genes comprise a Kunitz protease inhibitor domain encoding exon, and another exon within the divergent regions adjacent to the transmembrane domain, i.e. exon 15 of the APP gene and an exon encoding 12 residues in APLP2. Omission of the latter exons in L-APP and L-APLP2 isoforms, respectively, generates a functional recognition sequence for xylosyltransferase-mediated addition of glycosaminoglycans and proteoglycan formation. In this paper, we summarize our analyses of the regulated expression of these alternatively spliced exons in APP and APLP2 in primary cultured rat brain cells, rat brain development and aging. In conjunction with additional data for the human brain, these data provide important clues for understanding the functional significance of alternative splicing and glycosylation in APP biology. On the basis of recent results showing a higher amyloidogenicity of exon 15 encoding APP than L-APP isoforms, we further discuss the potential significance of the low levels of L-APP in neurons for the susceptibility of the brain towards Alzheimer's disease.
阿尔茨海默病β A4-淀粉样蛋白前体（APP）和类APP蛋白（APLPs）是具有相似模块化结构域结构的跨膜糖蛋白。在这两个基因中发现的可变剪接外显子包括一个编码库尼茨蛋白酶抑制剂结构域的外显子，以及另一个位于跨膜结构域相邻的差异区域内的外显子，即APP基因的外显子15和APLP2中编码12个残基的一个外显子。分别在L-APP和L-APLP2异构体中缺失后一个外显子，会产生一个功能性识别序列，用于木糖基转移酶介导的糖胺聚糖添加和蛋白聚糖形成。在本文中，我们总结了对原代培养大鼠脑细胞、大鼠脑发育和衰老过程中APP和APLP2中这些可变剪接外显子的调控表达的分析。结合人脑的其他数据，这些数据为理解APP生物学中可变剪接和糖基化的功能意义提供了重要线索。基于最近的结果表明，编码APP的外显子15比L-APP异构体具有更高的淀粉样蛋白生成能力，我们进一步讨论了神经元中低水平的L-APP对大脑易患阿尔茨海默病的潜在意义。
