Sphingosine-1-phosphate and Alzheimer's disease

1-磷酸鞘氨醇和阿尔茨海默病

• 批准号: 172556834
• 负责人: Privatdozentin Dr. Gerhild van Echten-Deckert, Ph.D.
• 金额: --
• 依托单位: Abteilung Biochemie der Lipide
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/172556834?language=en
• 关键词: Sphingosine; phosphate; Alzheimer; disease

Sphingosine-1-phosphate (S1P) regulates a wide range of cellular processes including proliferation, differentiation, motility, cytoskeleton rearrangements and calcium homeostasis. Although S1P promotes cell survival in peripheral tissues, increased S1P levels appear to be toxic in terminally differentiated primary neurons. Intriguingly, S1P dependent neurotoxicity shows similarity to that of the amyloid ß-peptide (Aß), which constitutes amyloid plaques, characteristic for Alzheimer’s disease (AD). Both S1P and Aß induce an aberrant reactivation of cell cycle events. Preliminary experiments demonstrate a functional relation of S1P and the ß-amyloid precursor protein (APP). The accumulation of S1P in S1P-lyase deficient cells induces increased expression of APP and affects its proteolytic processing. The central aim of this project is to identify and characterize molecular mechanisms that underlie the S1P dependent metabolism of APP and neuronal death.

鞘氨醇-1-磷酸（S1 P）调节广泛的细胞过程，包括增殖、分化、运动、细胞骨架重排和钙稳态。虽然S1 P促进外周组织中的细胞存活，但增加的S1 P水平在终末分化的原代神经元中似乎是有毒的。有趣的是，S1 P依赖性神经毒性显示出与淀粉样蛋白β-肽（A β）的相似性，其构成阿尔茨海默病（AD）的特征性淀粉样蛋白斑块。S1 P和A1 P均诱导细胞周期事件的异常再活化。初步实验证实了S1 P和β-淀粉样前体蛋白（APP）的功能关系。S1 P裂解酶缺陷细胞中S1 P的积累诱导APP表达增加并影响其蛋白水解加工。该项目的主要目的是识别和表征APP和神经元死亡的S1 P依赖性代谢的分子机制。