Exogenous IGF-1 improves tau pathology and neuronal pyroptosis in high-fat diet mice with cognitive impairment

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.