PRESENILIN-1 IN DEVELOPMENT AND AGING

PRESENILIN-1 在发育和衰老中的作用

• 批准号: 6540258
• 负责人: Hui Zheng
• 金额: $ 29.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-20 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540258
• 关键词: Mus musculus; aging; amyloid proteins; biological signal transduction; cadherins; central nervous system; developmental neurobiology; embryo /fetus tissue /cell culture; gene deletion mutation; gene expression; gene targeting; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; membrane transport proteins; mutant; northern blottings; phenotype; presenilin; protein biosynthesis; protein protein interaction; protein structure function; skin; western blottings

Mutations in Presenilin-1 (PS1) are linked to early onset of familial Alzheimer's disease (FAD) and lead to increased production of Abeta42, a peptide that is accumulated during aging and plays a critical role in AD pathogenesis. PS1 is a multi- pass transmembrane protein that is essential for mouse embryonic development and is required for Abeta peptide generation. PS1 also interacts with beta-catenin and has been implicated in regulating beta-catenin stability in vitro. The in vivo function of PS1 in the adult central nervous system and other tissues is poorly understood, due to the early lethal phenotype of the PS1 null mouse. We have reported that transgenic mouse lines expressing either the wild-type human PS1 protein or PS1 containing the A246E FAD mutation, under the neuronal-specific human Thy-1 promoter, can protect the PS1 null mouse against embryonic lethality and simultaneously restore Abeta expression. This "rescue" system allows us to further define PS1 in vivo activities by introducing specific modifications, such as PS1 mutations affecting Abeta synthesis or beta-catenin interaction respectively. It also offers us a unique opportunity to study the effect of PS1 loss-of-function in adult peripheral tissues of existing mice as they are rescued by a neuronal specific expression of the PS1 transgene. Our preliminary data indicate that lack of PS1 expression in the skin of these mice leads to epidermal hyperplasia and neoplasm, suggesting that PS1 may play an important role in skin tissue, possibly through beta-catenin signaling pathway. Our long-term objective is to use our established rescue system to dissect multiple pathways which PS1 seems to participate in vivo. The specific aims of the proposal are: 1] To explore the molecular mechanism of PS1 activity in adult epidermis; 2] To identify the in vivo significance of PS1- beta-catenin interaction; 3] To determine whether the developmental activity and Abeta generating property of PS1 can be differentiated. We believe that these studies will advance our understanding of the physiological function of PS1 and the pathogenic mechanism of Alzheimer's disease.

Presenilin-1（PS1）的突变与家族性阿尔茨海默氏病（FAD）的早期发作有关，并导致Abeta42的产生增加，Abeta42是在衰老过程中积累的肽，在AD发病机理中起关键作用。 PS1是一种多通过的跨膜蛋白，对于小鼠胚胎发育至关重要，是Abeta肽产生所必需的。 PS1还与β-连环蛋白相互作用，并与体外调节β-catenin稳定性有关。 由于PS1无效小鼠的早期致死表型，对成年中枢神经系统和其他组织中PS1的体内功能知之甚少。 我们报道说，在神经元特异性的人THY-1启动子下，表达野生型人PS1蛋白或含有A246E FAD突变的转基因小鼠系可以保护PS1无效小鼠免受胚胎杀伤力，并同时恢复ABETA的表达。这种“救援”系统使我们能够通过引入特定的修饰，例如分别影响ABETA合成或β-catenin相互作用的PS1突变来进一步定义PS1。 它还为我们提供了一个独特的机会，可以研究现有小鼠的成人外周组织PS1功能丧失的影响，因为它们是通过PS1转基因的神经元特异性表达挽救的。 我们的初步数据表明，这些小鼠的皮肤中缺乏PS1表达会导致表皮增生和肿瘤，这表明PS1可能在皮肤组织中起重要作用，可能通过β-catenin信号通路。 我们的长期目标是利用我们既定的救援系统来剖析PS1似乎参与体内的多种途径。 该提案的具体目的是：1]探索成人表皮中PS1活性的分子机制； 2]确定pS1-β-蛋白酶相互作用的体内意义； 3]确定PS1的发展活动和Abeta产生特性是否可以区分。 我们认为，这些研究将提高我们对PS1生理功能的理解和阿尔茨海默氏病的致病机制。