Effekte des MAP Kinase Inhibitors CNI-1493 auf Amyloid beta behandelte primäre mikrogliäre und neuronale Zellen

Alzheimer´s Disease (AD) is a progressive neurodegenerative disorder of the central nervous system. It is a disease of the old age (with a prevalence of approximately 6% among patients over 65 years) leading to severe physical and mental disability. Soluble and insoluble aggregates of Amyloid β (Aβ) and tau protein play an important role in the pathogenesis of AD. By disrupting neuronal function these proteinaceous agents cause pronounced neurodegeneration. Secondary to neurodegeneration, glial cells are activated in a process referred to as neuroinflammation. Glial activation further aggravates neurodegeneration. This thesis examines the effects of CNI-1493 on Aβ treated primary neurons and microglia. CNI-1493 is a tetravalent guanyl hydrazone inhibiting the phosphorylation of p38 MAPK. Thus, the compound has an anti-inflammatory effect by attenuating cytokine secretion from monocytes and macrophages. CNI-1493 has already been tested in a transgenic mouse model. It was shown to improve cognitive performance and reduce Aβ plaque load in the brains of treated animals. In Aβ treated primary neuronal cultures, pretreatment with CNI-1493 caused an upregulation of the purinergic nucleotide receptors type P2Y2 (P2Y2R). This receptor is inflammation controlled. So far, several publications identified the cytokine IL-1β as a potent inducing agent of this receptor. Activation of P2Y2R has different positive implications in the context of AD pathology. Additionally, secretion of cytokines from Aβ treated microglia was assessed using ELISA. Treatment with CNI-1493 (2.5 µM) decreased Aβ induced secretion of the proinflammatory cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor α (TNF α). At the same time, there was a pronounced increase of the likewise proinflammatory cytokine IL-1β. CNI-1493 induced reduction of TNF α and IL-6 alongside with increased IL-1β levels is an effect that was not described so far. We assume the favorable effects of CNI-1493 previously found in the mouse model were not only due to suppresion of TNF α and IL-6 but probably also because of the induction of IL-1β. These results are in line with other studies showing neuroprotective effects of IL-1β in the context of AD pathology.