Glutaminyl cyclase inhibitor exhibits anti-inflammatory effects in both AD and LPS-induced inflammatory model mice

Abstract Up-regulated glutaminyl cyclase (QC) plays crucial roles in the initiation of Alzheimer's disease (AD) and kinds of chronic diseases mediated by inflammation. QC is supposed as a novel target for the therapeutics of these diseases. Here, we explored the anti-inflammation effects of diphenyl conjugated imidazole (DPCI) derivatives which were previously designed, synthesized and evaluated as novel QC inhibitors for AD treatment in our lab. Behavioral tests, QC activity assay, histology and ELISA analysis were conducted on both AD and lipopolysaccharides (LPS)-induced inflammatory model mice. It was shown that behavioral and cognitive performance in AD mice treated with the selected compound DPCI-23 were enhanced notably. QC activity, the formation of pE-Aβ and Aβ plaques and the activation of astrocytes and microglia cells in AD mice brains were inhibited, and the levels of inflammatory factors such as IL-6, IL-1β and TNF-α in serum were reduced remarkably. Furthermore, elevated QC activity in inflammatory mice brains was also inhibited, and levels of IL-1β, IL-1ra, TNF-α and CCL2 in serum, kidneys and brains together with the activated astrocytes and microglia cells in brains were all repressed significantly after the treatment of DPCI-23. These findings observed in this research demonstrated the anti-inflammation potency of DPCI-23 in modal of AD and inflammation by inhibiting QC activity, and may contribute to the employment of QC inhibitors for the prevention and treatment of AD and other inflammatory diseases.