APP-RELATED GENES AND ALZHEIMER'S DISEASE

最近的证据表明，淀粉样蛋白p蛋白前体（APP）基因 是一个高度保守的相关基因家族的成员。一个类APP 基因（APPL）已经从果蝇中分离出来，另一个基因已经被 以从大鼠睾丸分离的部分cDNA的形式报道。更 最近，我们的实验室分离了编码两种新的 APP样蛋白（淀粉样蛋白受体样蛋白，APLP 1和APLP 2）。 这些蛋白质在氨基酸水平上与APP高度同源。的 β-A4结构域在APLP 1和APLP 2中仅部分保守，然而， 氨基酸一致性和特异性的显著保守程度 该蛋白质家族内的结构域表明，这些蛋白质可能共享 共同的功能，也许与共同的因素， 参与蛋白质加工和基因调控。基于我们 初步研究结果，我们提出，生产，成熟， APP，APLP 1和APLP 2在神经元中的代谢，其中这些蛋白质 似乎是共同表达的，可能是临界平衡的。我们假设 APP、APLP 1和APLP 2信息的化学计量的变化，和/或 蛋白质有效地将APP转移到替代代谢途径 包括易形成淀粉样蛋白的那些。我们绘制了 人APLP 2基因至11号染色体，APLP 1基因至近端长 在人类19号染色体的臂上，也有一种迟发性FAD， 指定使APLP成为该基因缺陷的绝佳候选者。我们 建议进一步确定APLP 1和APLP 2的特征，并分离其他成员 APP样基因家族，同时比较基因表达， 调节和加工这些蛋白质。我们选择探索 APLP家族在DNA、RNA和蛋白质水平上的作用，因为我们相信， 这些新的蛋白质的潜在重要性的病因学 阿尔茨海默病和衰老值得这样一个迅速的全面评估。 我们充分认识到， APLP家庭的处理可能涉及以下赠款建议： 自己的.因此，我们设计了一系列实验， 以有重点的方式提供每个领域的关键数据点 调查。实验的最终目标是 提供一个基本的数据集，评估 APLP基因家族在阿尔茨海默病发病过程中的作用及其与年龄的关系 神经变性

Recent evidence indicates that the amyloid p protein precursor (APP) gene is a member of a highly conserved family of related genes. An APP-like gene (APPL) has been isolated from Drosophila and another has been reported in the form of a partial cDNA isolated from rat testes. More recently, our laboratory has isolated human cDNA clones encoding two novel APP-like proteins (amyloid precursor-like proteins, APLP1 and APLP2). These proteins are highly homologous to APP at the amino acid level. The beta-A4 domain is only partially conserved in APLP1 and APLP2, however, the remarkable degree of conservation of amino acid identity and specific domains within this protein family suggest that these proteins may share common functions, and, perhaps interact with common factors that are involved with protein processing and gene regulation. Based on our preliminary findings, we propose that production, maturation, and metabolism of APP, APLP1, and APLP2 in neurons in which these proteins appear to be co-expressed, may be critically balanced. We hypothesize that changes in the stoichiometry of APP, APLP1, and APLP2 message and/or protein effectively divert APP into alternative metabolic pathways including those predisposed toward amyloid formation. We have mapped the human APLP2 gene to chromosome 11, and the APLP1 gene to the proximal long arm of human chromosome 19 where a late-onset form of FAD has also been assigned making APLP an excellent candidate for this gene defect. We propose to further characterize APLP1 and APLP2 and isolate other members of the APP-like gene family, concurrently comparing gene expression, regulation, and processing of these proteins. We have chosen to explore the APLP family at the DNA, RNA and protein levels because we believe that the potential importance of these novel proteins in the etiology of Alzheimer's disease and aging deserves such a prompt overall assessment. We fully appreciate that comprehensive studies of expression, regulation and processing of the APLP family could each entail grant proposals of their own. Therefore, we have devised a set of experiments aimed at providing in a focused manner, critical data points in each of these areas of investigation. The ultimate goal of the experiments proposed is to provide a rudimentary data set assessing the potential roles played by the APLP gene family in the process of Alzheimer- and age-related neurodegeneration.