Exogenous IGF-1 improves tau pathology and neuronal pyroptosis in high-fat diet mice with cognitive impairment
Abstract Background Insulin-like growth factor-1 (IGF-1) improves obesity-induced cognitive impairment, but its mechanism is not fully clarified. The aim of the study was to reveal whether IGF-1 treated cognitive impairment by improving tau pathology and neuronal pyroptosis in high-fat diet mice, and to further explore its molecular mechanisms involved.Methods During in vitro experiment, C57BL/6J mice were fed with high-fat diet, and were treated with PEG-IGF-1, IGF-1 receptor blocker AXL1717, HO-1 blocker Znpp IX or their combinations. Cognitive function was evaluated using Morris water maze. Expression of Nrf-2, HO-1, p-tau, NLRP3, Caspase-1 and IL-1β in hippocampus was determined using western blotting. Pyroptosis rate in hippocampus was measured using flow cytometry. During in vivo experiment, HN-h cells were treated with palmic acid, pyroptosis blocker nonecrosulfonamide or their combinations. The expression of the proteins and pyroptosis rate were also measured using western blotting and flow cytometry.Results During in vitro experiment, high-fat diet mice showed cognitive impairment, hyperphospharylation of tau protein and significant neuronal pyroptosis in hippocampus compared with the sham mice. After exogenous IGF-1 treatment, these abnormalities were reversed, and Nrf-2/HO-1 signaling pathway was activated. Inhibition of such signaling pathway using IGF-1 receptor blocker or HO-1 blocker re-deteriorated cognitive function, neuronal pyroptosis and tau pathology in hippocampus. During in vivo experiment, inhibition of pyroptosis using its blocker improved tau pathology in palmic acid-treated HN-h cells. Conclusion Exogenous IGF-1 improved cognitive impairment, tau pathology and neuronal pyroptosis induced by high-fat diet through activation of Nrf-2/HO-1 signaling pathway.