Subproject A

(M. Heneka, University Clinic of Bonn; M. Hüll, University Clinic of Freiburg)

Inflammation plays an important role in Alzheimer’s disease. Under pathological conditions, microglia become activated, migrate to the site of damage ( migration ) and clear cellular debris from the brain ( phagocytosis ). It is therefore conceivable that an impairment of microglial key functions may significantly contribute to the disease pathogenesis of Alzheimer’s disease. In turn, induction of these salutary functions could exert beneficial effects.

NSAIDs and the PPARγ receptor agonists decrease Aβ load in the brain tissue of transgenic mice and increase phagocytosis of fibrillar Aβ in vitro. It is therefore plausible that the protective effect of NSAIDs and the PPARγ receptor agonists in Alzheimer’s disease rests on their ability to reduce the neurotoxic inflammatory effects activated by microglia while at the same time increasing microglial clearance function and motility.

In order to test this hypothesis, this subproject will examine to what extent various NSAIDs and PPAR-gamma agaonists can modulate microglia migration and the phagocytosis of Aβ peptides in vivo and in mouse models of Alzheimer’s disease.