Alzheimer Amyloid Precursor Protein cleavage regulation by Gangliosides

神经节苷脂对阿尔茨海默病淀粉样蛋白前体蛋白裂解的调节

• 批准号: 5436202
• 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: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5436202?language=en
• 关键词: Alzheimer; Amyloid; Precursor; Protein; cleavage

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.

AD 发病机制中的一个关键过程是 APP 被 a-、b- 和 g-分泌酶这三种蛋白酶降解，最终导致病理性 Ab42 以及许多其他与 AD 发病机制相关性大多不确定的分解产物的释放。了解这些蛋白水解活性是如何调节的至关重要，因为 Aß42 生成速率的任何增加都会对 AD 风险产生决定性影响。我们之前已经证明，g-和b-分泌酶活性与细胞胆固醇含量密切相关。 Fahrenholz 对α-分泌酶也发现了类似的结果。在一项初步研究中，我们现在筛选了几种不同的脂质，以进一步刺激 APP 分泌酶的活性。令人惊讶的是，我们发现一些神经节苷脂的刺激能力明显强于胆固醇。重要的是，这种效应是双向的，因为我们的结果还显示由于缺乏分泌酶活性而导致神经节苷脂成分失调。在这里，我们将高度集中地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。我们为阿尔茨海默病 Schwerpunkt 选择这个中等规模的项目是基于主题重要性和整合性、与 Schwerpunkt 内部合作伙伴的多重和协同互动以及该项目确实可以在剩余两年资助年内完成的可能性。