Alzheimer Amyloid Precursor Protein cleavage regulation by Gangliosides

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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.