Subproject C

(G. Multhaup, FU Berlin; D. Langosch, TU Munich)

The formation of Aβ42 via gamma-secretases is significantly determined by substrate/enzyme recognition. We have identified and analyzed an interaction motif within the transmembrane segment of the Aβ precursor protein responsible for a dimerization of the substrate within the Aβ sequence. A targeted analysis of this GxxxG motif revealed that the proteolytic Aβ42 processing is amplified by a dimerization but that a weakening of the dimerization allows less Aß42 and therefore smaller peptides to form. Independently, Aβ42-lowering NSAIDs ( gamma-secretase modulators ) have been described to have almost an identical affect on the formation of Aß42.

We are investigating the hypthothesis that gamma-secretase modulators can bind directly to the transmembrane sequence of the precursor protein and exude their effect via a weakening or strengthening of the dimerization. This sub-project aims to achieve an accurate explanation of the substrate/enzyme interaction in the presence of gamma-secretase modulators so as to understand their mechanisms on a molecular level and apply this knowledge to therapeutic approaches.

• With the help of BIACORE technology and ESI-MS analyses it should be clarified whether and how gamma-secretase modulators bind to the Aß sequence and the GxxxB motive.

• The bacterial system will be examined to see whether gamma-secretase modulators in a biological membrane can modulate the dimerization of the Aß42 precursor protein.

• Mouse models are to be developed for in vivo tests to analyse the preventative effect of optimized gamma-secretase modulators.