Subproject B

(S. Weggen, University Clinic of Düsseldorf; B. Bulic, MPI Dortmund; H. Waldmann, MPI Dortmund)

The increased production and aggregation of Aß42 peptides in the brain is an early and causal step in the development of Alzheimer’s disease. The γ-secretase enzyme catalyzes the final step in the generation of Aβ peptides. However, pharmacological measures aimed at completely inhibiting gamma-secretase activity resulted in toxic side effects.

Some compounds in the group of non-steroidal anti-inflammatory drugs ( NSAIDs ) for example sulindac sulfide and ibuprofen, possess selective Aβ42-lowering activity that does not interfere with other physiological functions of gamma-secretases. These Aβ42-lowering NSAIDs ( gamma-secretase modulators ) could therefore be chemical leads to a new generation of drugs that block the causal mechanisms of Alzheimer’s disease.

Unfortunately, current Aβ42-lowering NSAIDs suffer from pharmacological shortcomings such as low potency against Aβ42, low brain permeability, and potent anti-inflammatory effect (COX activity), which in long-term use is associated with clinical side effects. Therefore there is an urgent need for the development of new gamma-secretase modulators with optimized pharmacological characteristics.

Using combinatorial chemistry methods and cell biological and animal experimental approaches this sub-project has the following aims:

• to analyze and optimize the chemical structure of the gamma-secretase modulator sulindac sulfide, putting special emphasis on increasing Aβ42-lowering activity and completely removing COX activity.

• to clarify whether the anti-inflammatory properties (COX-activity) of current Aβ42-lowering NSAIDs contribute to their preventive effects or are expendable in mouse models of Alzheimer’s disease.