BackgroundInsulin-like growth factor-1 (IGF-1) improves obesity-induced cognitive impairment, but its mechanism is not fully clari ed. 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.
MethodsDuring 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 ow 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 ow cytometry.
ResultsDuring in vitro experiment, high-fat diet mice showed cognitive impairment, hyperphospharylation of tau protein and signi cant 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 redeteriorated 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.
ConclusionExogenous IGF-1 improved cognitive impairment, tau pathology and neuronal pyroptosis induced by highfat diet through activation of Nrf-2/HO-1 signaling pathway.
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