Sphingosine-1-phosphate and Alzheimer's disease

鞘氨醇-1-磷酸(S1P)调节着广泛的细胞过程，包括增殖、分化、运动、细胞骨架重排和钙稳态。尽管S1P促进了外周组织中的细胞存活，但增加的S1P水平似乎对终末分化的初级神经元是有害的。有趣的是，S1P依赖的神经毒性与淀粉样多肽(A？)相似，后者构成淀粉样斑块，是阿尔茨海默病(AD)的特征。S1P和A？都能诱导细胞周期事件的异常重新激活。初步实验证实了S1P与β-淀粉样前体蛋白(APP)之间的功能关系。S1P裂解酶缺陷细胞中S1P的积累导致APP表达增加，并影响其蛋白降解过程。该项目的中心目标是识别和表征APP依赖S1P代谢和神经元死亡的分子机制。

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.