Neuroprotective Properties of Apo6856, a Novel Hydroxypyridinone Iron Chelator, in Alzheimer’s Disease (P5.208)

Objective: We sought to evaluate the neuroprotective properties of a novel hydroxypyridinone Apo6856, an analog of the FDA-approved iron chelator deferiprone, in SH-SY5Y and MC-65 human neuronal cells, and in a transgenic (TG) mouse model of Alzheimers disease (AD). Background: Neuroprotective properties of deferiprone have been demonstrated earlier in vitro and in vivo, as well as in Parkinsons disease clinical trials. Methods: Neuroprotective effect of Apo6856 against oxidative stress was investigated in H2O2 challenged SH-SY5Y human neuronal cells. Protection against Aβ toxicity was studied in the MC-65 human neuronal cells, overexpressing Aβ. The effects of treatment on memory of the TG mice overexpressing human APPswe/PS1dE9 were assessed in the Radial Arm Water Maze (RAWM) test. Expression of genes involved in neurodegeneration, anti-inflammatory and anti-oxidant pathways was assessed by Real-Time qPCR gene arrays, Western blotting, ELISA and immunohistochemistry. Nrf2 activity was assessed by dual luciferase reporter assay. Results: Apo6856 concentration-dependently protected SH-SY5Y cells from H2O2-induced oxidative stress by inhibiting ROS production. It also rescued MC-65 cells from Aβ-induced cell death. The treatment caused a concentration- and time-dependent up-regulation of Nrf2 activity in SH-SY5Y cells and modulated the expression of BNIP3, EPHX2, CDKN1A, FOXM1, IL1A/B, NOX4 and CYBB genes in a pattern consistent with downregulation of inflammation and ROS production, and increased cellular antioxidant defense capacity. In the APPswe/PS1dE9 mice, Apo6856 improved working and reference memory. The treatment reduced the levels of Aβ, and the expression of inflammatory markers GFAP and NFκB in the AD mouse brain, but was without significant effect on brain iron deposition. Conclusion: Apo6856 demonstrated neuroprotective properties in cellular and animal models of AD. The effect is mediated by inhibition of ROS production and inflammation and up-regulation of cellular antioxidant defenses. Disclosure: Dr. Premyslova has received personal compensation for activities with Apopharma as an employee. Dr. Xu has nothing to disclose. Dr. Wang has received personal compensation for activities with ApoPharma as an employee. Dr. Xiong has nothing to disclose. Dr. Nitia-Nootan has nothing to disclose. Dr. Deosaran has received personal compensation for activities as an employee. Dr. Peng has nothing to disclose. Dr. Callaghan has nothing to disclose. Dr. Zang has nothing to disclose. Dr. Rabadia has nothing to disclose. Dr. Feeney has received personal compensation for activities with ApoPharma as an employee. Dr. Wodzinska has received personal compensation for activities with ApoPharma as an employee. Dr. Spino has nothing to disclose. Dr. Connelly has nothing to disclose.