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

我们最近发现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也具有生理功能。我们最近的数据表明，APP的功能不仅限于鞘磷脂酶，但其他鞘脂酶的APP以及调节。对于GD 3-synthase（GD 3S），我们可以阐明APP是如何调节该酶的机制的。淀粉样蛋白β（Aβ）通过调节底物的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GD 3S之外，还鉴定了至少3种鞘脂酶，这表明了一种共同的机制。本项目的重点是研究APP对其他酶的调节机制，并阐明Aβ和AICD依赖性调节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依赖性改变将直接影响突触功能-本提案的另一个目标。将使用细胞培养、无细胞试验和敲除动物进行研究，以验证体内相关性。预期是更好地了解APP在鞘脂稳态中的作用，可能导致新的治疗方法。

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.