ALZHEIMER'S DISEASE RELATED PRESENILINS

阿尔茨海默病相关早老素

• 批准号: 6540804
• 负责人: Mark E Fortini
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540804
• 关键词: Commonwealth of Independent States; Drosophilidae; amyloid proteins; apoptosis; developmental neurobiology; genetic regulation; genetically modified animals; presenilin

Mutant human Presenilins influence the proteolysis of amyloid precursor protein (APP), causing an accelerated accumulation of neurotoxic amyloid peptides in Alzheimer's disease. In the model organisms Caenorhabditis, Drosophila, and the mouse, Presenilins are required for Notch/Lin-12 developmental signaling. Presenilins regulate key proteolytic processing events during Notch receptor maturation and signaling that may be analogous to the Presenilin-dependent cleavages of APP in Alzheimer's disease. Presenilins have also been implicated in the cellular response to neurodegenerative apoptotic stimuli in both mammalian cells and Drosophila. In this FIRCA application, transgenic Drosophila will be generated that overexpress both wild-type and Alzheimer's disease-associated Presenilins. The functional properties of transgenic Presenilins will be assessed by several criteria, including analysis of developmental and adult phenotypes, interactions with Notch pathway genes, effects on Notch receptor processing, and induction of apoptosis. Human Presenilins (PS1 and 2) as well as human APP will also be functionally characterized in this transgenic model. These studies will be coupled with parallel tests of the wild-type and mutant proteins in mammalian neuronal cell culture to assess the degree of functional similarity between Drosophila and human Presenilins. The possibility that Presenilin genes are transcriptionally regulated by Notch signaling output will also be tested using these models. These studies will determine if Presenilin is a component of the feedback mechanism known to operate on the Notch pathway. Finally, Drosophila Presenilin mutants and other new mutants that interact with Presenilin will be systematically examined for adult learning and memory deficits, extending the developmental analysis of these mutants that is already underway. This well-defined set of proposed studies seeks to evaluate the utility of Drosophila as a transgenic model for functional analysis of human Presenilins, and to uncover conserved activities of fly and human Presenilins in apoptosis, neurogenesis, and neurodegeneration that occur during early development as well as during later learning and memory consolidation. The studies proposed here will clarify the in vivo activity of Presenilin in the processing of Notch, APP, and other proteins, and may ultimately increase our understanding of the molecular causes of Alzheimer's disease and its accompanying memory decline in humans.

突变的人类寄生虫会影响淀粉样蛋白前体蛋白（APP）的蛋白水解，从而导致神经毒性淀粉样蛋白肽在阿尔茨海默氏病中加速积累。 在模型生物体中，果蝇和小鼠的生物体中，Notch/Lin-12发育信号传导需要presenilins。老年蛋白调节在Notch受体成熟和信号传导过程中的关键蛋白水解处理事件，可能类似于APP在阿尔茨海默氏病中的依赖性蛋白依赖性裂解。哺乳动物细胞和果蝇对神经退行性凋亡刺激的细胞反应也与细胞反应有关。在此FIRCA应用中，将产生过表达野生型和阿尔茨海默氏病相关的presenilins的转基因果蝇。 转基因presenilins的功能特性将通过几个标准进行评估，包括分析发育和成人表型，与Notch途径基因的相互作用，对Notch受体加工的影响以及凋亡的诱导。 人类presenilins（PS1和2）以及人类应用在此转基因模型中也将在功能上表征。 这些研究将与哺乳动物神经元细胞培养中的野生型和突变蛋白的平行检测结合，以评估果蝇和人类presenilins之间功能相似性的程度。在这些模型上，还将测试Presenilin基因受Notch信号输出的转录调节的可能性。 这些研究将确定Presenilin是否是已知在Notch途径上运行的反馈机制的组成部分。 最后，将系统地检查果蝇presenilin突变体和其他与Presenilin相互作用的新突变体的成人学习和记忆缺陷，从而扩展了已经正在进行的这些突变体的发育分析。这项明确定义的一组拟议的研究旨在评估果蝇作为人类presenilins功能分析的转基因模型的实用性，并发现在早期发展期间以及后来的学习和记忆过程中发生的苍蝇和人培养地的保守活性。 此处提出的研究将阐明老年蛋白在槽口，APP和其他蛋白质加工中的体内活性，并最终可能会增加我们对阿尔茨海默氏病的分子原因及其伴随的记忆下降的理解。