Subproject D

(C. Pietrzik, University of Mainz; C. Kuhlmann, University of Mainz)

The accumulation of Aß42 peptides in the brain is a causal step in the pathogenesis of Alzheimer’s disease. These peptides have a distinct tendency to aggregate, small aggregates ( oligomers ) being particularly damaging to cells. Aß oligomers are in balance with single Aß peptides (monomers). However, little is known about the relgulation of this equilibrium and the physiological breakdown of the oligomers.

The blood-brain barrier is a natural barrier in the body regulating the transport of molecules in and out of the brain. Aß peptides and drugs such as non-steroidal anti-inflammatory drugs ( NSAIDs ) are unable to pass the blood-brain barrier. Aß peptides can only leave the brain to the bloodstream via special transporters, and are taken via the bloodstream to the liver where they are broken down. One important open question is whether Aß oligomers can be transported over the blood-brain barrier or whether they first have to be separated into monomers. This sub-project has the following aims:

• to establish an in vitro transport system and model of the blood-brain barrier, and then subsequently to determine the transport kinetics of Aß42 oligomers and also NSAIDs through the blood-brain barrier.

• to identify, by means of transport studies with NSAID-like molecules, new chemical structures that have heightened ability to enter and leave the brain.

• to better characterize the mechanisms of Aß peptide transport through the blood-brain barrier and to explain whether NSAIDs can influence transport through the blood-brain barrier by effecting these mechanisms.