Role of the Alzheimer's Disease Enzymes and Proteins in Sphingolipid and Glycosphingolipid Homeostasis

阿尔茨海默病酶和蛋白质在鞘脂和糖鞘脂稳态中的作用

• 批准号: 39134157
• 负责人: Professor Dr. Tobias Hartmann
• 金额: --
• 依托单位: Deutsches Institut für Demenzprävention (DIDP)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/39134157?language=en
• 关键词: Role; Alzheimer; Disease; Enzymes; Proteins

We recently showed the link between sphingomyelinase and the Amyloid precursor protein (APP). Beside its detrimental role in Alzheimer´s disease, this showed for the first time that APP also has a physiological function. Our recent data suggest that the APP function is not limited to sphingomyelinases, but that other sphingolipid enzymes are regulated by APP as well. For the GD3-synthase (GD3S) we could elucidate the mechanism how this enzyme is regulated by APP. Whereas Amyloid-β (Aβ) directly regulates enzyme activity by modulating substrate availability, the APP intracellular domain (AICD) regulates the expression level of the enzyme. Beside the GD3S at least 3 more sphingolipid enzymes were identified, which suggest a common mechanism. Focus of this project is to investigate the mechanism how the other enzymes are regulated by APP, and to elucidate the potential general mechanism of Aβ and AICD dependent regulation in sphingolipid homeostasis. As sphingolipids play an abundant role in synaptic processes, APP dependent alterations will directly affect synaptic function - another goal of this proposal. Studies will be done with cell culture, cell free assays and knock out animals to validate in vivo relevance. Expected is a better understanding the role of APP in sphingolipid homeostasis, possibly leading to new therapeutic approaches.

我们最近展示了鞘磷脂酶和淀粉样前体蛋白（APP）之间的联系。除了在阿尔茨海默病中的有害作用外，这首次表明APP还具有生理功能。我们最近的数据表明，APP的功能不仅限于鞘磷脂酶，而且其他鞘脂酶也受到APP的调节。对于gd3合成酶（GD3S），我们可以阐明APP如何调节该酶的机制。淀粉样蛋白-β (Aβ)通过调节底物利用率直接调节酶的活性，而APP胞内结构域（AICD）调节酶的表达水平。除了GD3S，至少还有3种鞘脂酶被发现，这表明了一种共同的机制。本课题的重点是研究APP对其他酶的调控机制，并阐明Aβ和AICD依赖性调控鞘脂稳态的潜在一般机制。由于鞘脂在突触过程中发挥着丰富的作用，APP依赖性的改变将直接影响突触功能，这是本研究的另一个目标。研究将通过细胞培养、无细胞测定和敲除动物来验证体内相关性。期望更好地理解APP在鞘脂稳态中的作用，可能导致新的治疗方法。