title: The role of CNI-1493 in the function of primary microglia with respect to amyloid-β.
abstract: Amyloid-β (Aβ) oligomer toxicity is a crucial factor in the development of Alzheimer's disease. Therefore, the aim of therapeutic research is to target the modification of secretase activity, increase Aβ degradation, reduce Aβ formation, and modulate Aβ-induced neuroinflammation. Recently, the p38 MAP kinase inhibitor CNI-1493 has been shown to reduce plaque load and has led to an improvement in memory performance in a transgenic mouse model. We examined the role of CNI-1493 in the microglial inflammatory response to Aβ using both a microglia cell line as well as primary microglia isolated from mesocortices. MTT assays were performed to quantify cell viability. FACS analysis was used to measure phagocytosis. We used ELISA to analyse cytokine concentrations in response to CNI-1493 treatment. Western-blot/Dot-blot techniques were used to show the interaction of CNI-1493 with Aβ-oligomers as well as to measure apoptosis in microglia cells. RT-PCR was used to analyze secretase expression, and secretase function was determined using fluorimetric assays. CNI-1493 is able to prevent oligomer formation as well as apoptosis in microglia. A significant reduction was found in the Aβ-induced release of IL-6 and TNF-α in the presence of CNI-1493. Phagocytosis is an essential Aβ removal mechanism and was enhanced by CNI-1493 in primary microglia. CNI-1493 also influenced the α-secretase product C83 with an increase in the treated cells, while a simultaneous reduction in Aβ secretion was also observed. We hypothesize that CNI-1493 not only reduces neuroinflammation and consequent neurodegeneration, but also leads to a shift in AβPP-processing towards the non-amyloidogenic pathway. Therefore, CNI-1493 is a promising candidate for the treatment of AD.
authors: Department of Neurology, Philipps-University Marburg, Marburg, Germany.
authors: Jan-Philipp
authors: JP
authors: Bach
authors: David
authors: D
authors: Mengel
authors: Tina
authors: T
authors: Wahle
authors: Andreas
authors: A
authors: Kautz
authors: Monika
authors: M
authors: Balzer-Geldsetzer
authors: Yousef
authors: Y
authors: Al-Abed
authors: Richard
authors: R
authors: Dodel
authors: Michael
authors: M
authors: Bacher