The intramembrane proteolysis of the Amyloid Precursor Protein (APP) is the final step in the release of the amyloid peptide, the major constituent of the amyloid plaques in Alzheimer's disease. The protease complex responsible for this proteolytic event consists of Presenilin 1 or 2, Nicastrin, Aph1a or Aph1b, and Pen 2.
It is presently not known whether different gamma-secretase complexes exist or whether there is tissue and/or substrate specificity of these complexes. It is also unclear whether other proteins are involved in the regulation or activation of the complex. The current proposal aims to address the question on the function of Aph1a and b using cell biological and biochemical approaches in yeast, Mus Musculus and derived cell lines.
The results of this research will have implications for the better understanding of the novel cellular mechanism of regulated intramembrane proteolysis, and could also profoundly affect strategies to cure Alzheimer's disease aiming at lowering amyloid peptide production by targeting gamma-secretase processing of APP in a more specific way at the level of gamma-secretase.
Fields of science
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