Alzheimer Amyloid Precursor Protein cleavage regulation by Gangliosides

AD发病的一个关键过程是APP被三种蛋白酶A -、b-和g-分泌酶降解，最终导致病理性Ab42的释放，以及许多其他与AD发病机制相关性不确定的分解产物。了解这些蛋白水解活性是如何被调节的是至关重要的，因为a ß42产生率的任何增加对患AD的风险都有决定性的影响。我们以前已经表明，g-和b-分泌酶活性与细胞胆固醇含量密切相关。法伦霍兹在a-分泌酶上也发现了类似的结果。在初步研究中，我们现在筛选了几种不同的脂质，以进一步刺激APPsecretases的活性。令人惊讶的是，我们发现一些神经节苷脂具有明显强于胆固醇的刺激能力。重要的是，这种影响是双向的，因为我们的结果也显示了由分泌酶活性缺乏引起的神经节苷脂组成的放松管制。在这里，我们将以高度集中的方式研究神经节苷脂如何参与app分泌酶的调节以及分泌酶如何影响神经节苷脂的组成。我们为阿尔茨海默Schwerpunkt选择了这个中等规模的项目，基于主题重要性和整合，Schwerpunkt内部合作伙伴的多重和协同互动，以及项目确实可以在剩余的两个资助年内完成的可能性。

A key process in the pathogenesis of AD is the degradation of the APP by three proteases, a-, b- and g-secretase, ultimately leading to the release of pathological Ab42, as well as a number of other breakdown products of mostly uncertain relevance to AD pathogenesis. It is crucial to understand how these proteolytic activities are regulated, because any increase in the rate of Aß42 production has a decisive impact on the risk to develop AD. We have shown before, that g- and b-secretase activities are closely connected to cellular cholesterol content. Similar results were found by Fahrenholz for a-secretase. In a preliminary study we now screened several different lipids for further stimulatory activities on APPsecretases. Surprisingly, we found that some gangliosides have stimulatory capacities significantly stronger than cholesterol. Importantly, this effect is bi-directional, as our results also show a deregulation of ganglioside composition caused by a lack of secretase activity. Here we will investigate in a highly focused approach how gangliosides take part in APP-secretases regulation and how secretases affect ganglioside composition. We selected this moderately sized project for the Alzheimer Schwerpunkt on the basis of thematic importance and integration, the multiple and synergistic interaction to partners inside of the Schwerpunkt and likelihood that the project can indeed be completed in the remaining two funding years.